Substituted n-phenyl-pyrrolidinylmethylpyrrolidine amides and therapeutic use thereof

ABSTRACT

The present invention discloses and claims a series of substituted N-phenyl-pyrrolidinylmethylpyrrolidine amides of formula (I). 
     
       
         
         
             
             
         
       
     
     Wherein R, R 1 , R 2 , R 3  and R 4  are as described herein. More specifically, the compounds of this invention are modulators of H3 receptors and are, therefore, useful as pharmaceutical agents, especially in the treatment and/or prevention of a variety of diseases modulated by H3 receptors including diseases associated with the central nervous system. Additionally, this invention also discloses methods of preparation of substituted pyrrolidinylmethylpyrrolidine amides and intermediates therefor.

CROSS REFERENCE TO RELATED APPLICATIONS

This application is a continuation of International application No.PCT/US2008/079,758, filed Oct. 14, 2008, which is incorporated herein byreference in its entirety; which claims the benefit of U.S. ProvisionalApplication No. 60/980,602, filed Oct. 17, 2007.

BACKGROUND OF THE INVENTION

1. Field of the Invention

The present invention relates to a series of substitutedN-phenyl-pyrrolidinylmethylpyrrolidine amides. The compounds of thisinvention are modulators of H3 receptors and are, therefore, useful aspharmaceutical agents, especially in the treatment and/or prevention ofa variety of diseases modulated by H3 receptors including diseasesassociated with the central nervous system. Additionally, this inventionalso relates to methods of preparation of substitutedN-phenyl-pyrrolidinylmethylpyrrolidine amides and intermediatestherefor.

2. Description of the Art

Histamine is a ubiquitous messenger molecule released from mast cells,enterochromaffin-like cells, and neurons. The physiological actions ofhistamine are mediated by four pharmacologically defined receptors (H1,H2, H3 and H4). All histamine receptors exhibit seven transmembranedomains and are members of the G-protein-coupled receptor superfamily(GPCRs).

The H1 receptor was the first member of the histamine receptor family tobe pharmacologically defined, with the development of classicalantihistamines (antagonists), such as diphenhydramine and fexofenadine.While antagonism of the H1 receptor of the immune system is commonlyused for the treatment of allergic reactions, the H1 receptor is alsoexpressed in various peripheral tissues and the central nervous system(CNS). In the brain, H1 is involved in the control of wakefulness, mood,appetite and hormone secretion.

The H2 receptor is also expressed in the CNS, where it may modulateseveral processes, including cognition. However, H2 receptor antagonistshave primarily been developed to ameliorate gastric ulcers by inhibitinghistamine-mediated gastric acid secretion by parietal cells. Classic H2antagonists include cimetidine, ranitidine, and famotidine.

It should further be noted that H4 receptor function remains poorlydefined, but may involve immune regulation and inflammatory processes.

H3 receptors have also been pharmacologically identified in the CNS,heart, lung, and stomach. The H3 receptor differs significantly fromother histamine receptors, exhibiting low sequence homology (H1: 22%,H2: 21%, H4: 35%). H3 is a presynaptic autoreceptor on histamine neuronsin the brain and a presynaptic heteroreceptor in nonhistamine-containingneurons in both the central and peripheral nervous systems. In additionto histamine, H3 also modulates the release and/or synthesis of otherneurotransmitters, including acetylcholine, dopamine, norepinepherin andserotonin. Of particular note, presynaptic modulation of histaminerelease by H3 allows significant regulation of H1 and H2 receptors inthe brain. Modulating multiple neurotransmitter signaling pathways, H3may contribute to varied physiological processes. Indeed, extensivepreclinical evidence indicates that H3 plays a role in cognition,sleep-wake cycle and energy homeostasis.

Modulators of H3 function may be useful in the treatment of obesity andcentral nervous system disorders (Schizophrenia, Alzheimer's disease,attention-deficit hyperactivity disorder, Parkinson's disease,depression, and epilepsy), sleep disorders (narcolepsy and insomnia),cardiovascular disorders (acute myocardial infarction), respiratorydisorders (asthma), and gastrointestinal disorders. See generally,Hancock, Biochem. Pharmacol. 2006 Apr. 14; 71(8):1103-13 and Esbenshadeet al. Mol. Interv. 2006 April; 6(2):77-88, 59.

Recently, compounds that are somewhat structurally related to thecompounds of the present invention have been disclosed to be melaninconcentrating hormone (MCH) receptor antagonists, see specifically U.S.Pat. No. 7,223,788. It should however be pointed out that there is nodisclosure as to the activity of the compounds disclosed therein at theH3 receptor site.

All of the references described herein are incorporated herein byreference in their entirety.

Accordingly, it is an object of this invention to provide a series ofsubstituted N-phenyl-pyrrolidinylmethylpyrrolidine amides as selectiveH3 receptor ligands for treatment of H3 receptor regulated CNSdisorders.

It is also an object of this invention to provide processes for thepreparation of the substituted N-phenyl-pyrrolidinylmethylpyrrolidineamides as disclosed herein.

Other objects and further scope of the applicability of the presentinvention will become apparent from the detailed description thatfollows.

SUMMARY OF THE INVENTION

Surprisingly, it has now been found that the compounds of formula (I)are useful as H3 receptor antagonists and/or inverse agonists. It shouldfurther be noted that the compounds of formula I are not encompassed bythe disclosure in U.S. Pat. No. 7,223,788. Moreover, unexpectedly it hasnow been found that the compounds of formula (I) are selectively activeonly at H3 receptors and exhibit low activity at the MCH-1 receptorsite, which aspect becomes even more apparent from the detaileddescription that follows. Thus in accordance with the practice of thisinvention there is provided a compound of formula (I):

wherein

-   R, R₁, R₂ and R₃ are the same or different and independently of each    other chosen from hydrogen, (C₁-C₄)alkyl or CF₃;-   R₄ is selected from the group consisting of phenyl, cyclohexyl,    pyridinyl, furanyl, isoxazolyl, quinolinyl, naphthyridinyl, indolyl,    benzoimidazolyl, benzofuranyl, chromanyl, 4-oxo-4H-chromenyl,    2,3-dihydro-benzofuranyl, benzo[1,3]dioxolyl and    2,5-dioxo-2,3,4,5-tetrahydro-1H-benzo[e][1,4]diazepinyl; wherein    said R₄ is optionally substituted one or more times with a    substituent selected from halogen, hydroxy, (C₁-C₄)alkyl,    (C₁-C₄)alkoxy, CF₃, hydroxymethyl, 2-hydroxyethylamino,    methoxyethylamide, benzyloxymethyl, piperidinyl,    N-acetyl-piperidinyl, pyrrolyl, imidazolyl and    5-oxo-4,5-dihydro-pyrazolyl.

This invention further includes various salts of the compounds offormula (I) including various enantiomers or diastereomers of compoundsof formula (I).

In other aspects of this invention there are also provided variouspharmaceutical compositions comprising one or more compounds of formula(I) as well as their therapeutic use in alleviating various diseaseswhich are mediated in-part and/or fully by H3 receptors.

DETAILED DESCRIPTION OF THE INVENTION

The terms as used herein have the following meanings:

As used herein, the expression “(C₁-C₆)alkyl” includes methyl and ethylgroups, and straight-chained or branched propyl, butyl, pentyl and hexylgroups. Particular alkyl groups are methyl, ethyl, n-propyl, isopropyland tert-butyl. Derived expressions such as “(C₁-C₄)alkoxy”,“(C₁-C₄)thioalkyl” “(C₁-C₄)alkoxy(C₁-C₄)alkyl”, “hydroxy(C₁-C₄)alkyl”,“(C₁-C₄)alkylcarbonyl”, “(C₁-C₄)alkoxycarbonyl(C₁-C₄)alkyl”,“(C₁-C₄)alkoxycarbonyl”, “amino(C₁-C₄)alkyl”, “(C₁-C₄)alkylamino”,“(C₁-C₄)alkylcarbamoyl(C₁-C₄)alkyl”,“(C₁-C₄)dialkylcarbamoyl(C₁-C₄)alkyl” “mono- ordi-(C₁-C₄)alkylamino(C₁-C₄)alkyl”, “amino(C₁-C₄)alkylcarbonyl”“diphenyl(C₁-C₄)alkyl”, “phenyl(C₁-C₄)alkyl”,“phenylcarboyl(C₁-C₄)alkyl” and “phenoxy(C₁-C₄)alkyl” are to beconstrued accordingly.

As used herein, the expression “cycloalkyl” includes all of the knowncyclic radicals. Representative examples of “cycloalkyl” include withoutany limitation cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl,cycloheptyl, cyclooctyl, and the like. Derived expressions such as“cycloalkoxy”, “cycloalkylalkyl”, “cycloalkylaryl”, “cycloalkylcarbonyl”are to be construed accordingly.

As used herein, the expression “(C₂-C₆)alkenyl” includes ethenyl andstraight-chained or branched propenyl, butenyl, pentenyl and hexenylgroups. Similarly, the expression “(C₂-C₆)alkynyl” includes ethynyl andpropynyl, and straight-chained or branched butynyl, pentynyl and hexynylgroups.

As used herein the expression “(C₁-C₄)acyl” shall have the same meaningas “(C₁-C₆)alkanoyl”, which can also be represented structurally as“R—CO—,” where R is a (C₁-C₃)alkyl as defined herein. Additionally,“(C₁-C₃)alkylcarbonyl” shall mean same as (C₁-C₄)acyl. Specifically,“(C₁-C₄)acyl” shall mean formyl, acetyl or ethanoyl, propanoyl,n-butanoyl, etc. Derived expressions such as “(C₁-C₄)acyloxy” and“(C₁-C₄)acyloxyalkyl” are to be construed accordingly.

As used herein, the expression “(C₁-C₆)perfluoroalkyl” means that all ofthe hydrogen atoms in said alkyl group are replaced with fluorine atoms.Illustrative examples include trifluoromethyl and pentafluoroethyl, andstraight-chained or branched heptafluoropropyl, nonafluorobutyl,undecafluoropentyl and tridecafluorohexyl groups. Derived expression,“(C₁-C₆)perfluoroalkoxy”, is to be construed accordingly.

As used herein, the expression “(C₆-C₁₀)aryl” means substituted orunsubstituted phenyl or naphthyl. Specific examples of substitutedphenyl or naphthyl include o-, p-, m-tolyl, 1,2-, 1,3-, 1,4-xylyl,1-methylnaphthyl, 2-methylnaphthyl, etc. “Substituted phenyl” or“substituted naphthyl” also include any of the possible substituents asfurther defined herein or one known in the art. Derived expression,“(C₆-C₁₀)arylsulfonyl,” is to be construed accordingly.

As used herein, the expression “(C₆-C₁₀)aryl(C₁-C₄)alkyl” means that the(C₆-C₁₀)aryl as defined herein is further attached to (C₁-C₄)alkyl asdefined herein. Representative examples include benzyl, phenylethyl,2-phenylpropyl, 1-naphthylmethyl, 2-naphthylmethyl and the like.

As used herein, the expression “heteroaryl” includes all of the knownheteroatom containing aromatic radicals. Representative 5-memberedheteroaryl radicals include furanyl, thienyl or thiophenyl, pyrrolyl,isopyrrolyl, pyrazolyl, imidazolyl, oxazolyl, thiazolyl, isothiazolyl,and the like. Representative 6-membered heteroaryl radicals includepyridinyl, pyridazinyl, pyrimidinyl, pyrazinyl, triazinyl, and the likeradicals. Representative examples of bicyclic heteroaryl radicalsinclude, benzofuranyl, benzothiophenyl, indolyl, quinolinyl,isoquinolinyl, cinnolyl, benzimidazolyl, indazolyl, pyridofuranyl,pyridothienyl, and the like radicals.

As used herein, the expression “heterocycle” includes all of the knownreduced heteroatom containing cyclic radicals. Representative 5-memberedheterocycle radicals include tetrahydrofuranyl, tetrahydrothiophenyl,pyrrolidinyl, 2-thiazolinyl, tetrahydrothiazolyl, tetrahydrooxazolyl,and the like. Representative 6-membered heterocycle radicals includepiperidinyl, piperazinyl, morpholinyl, thiomorpholinyl, and the like.Various other heterocycle radicals include, without limitation,aziridinyl, azepanyl, diazepanyl, diazabicyclo[2.2.1]hept-2-yl, andtriazocanyl, and the like.

“Halogen” or “halo” means chloro, fluoro, bromo, and iodo.

As used herein, “patient” means a warm blooded animal, such as forexample rat, mice, dogs, cats, guinea pigs, and primates such as humans.

As used herein, the expression “pharmaceutically acceptable carrier”means a non-toxic solvent, dispersant, excipient, adjuvant, or othermaterial which is mixed with the compound of the present invention inorder to permit the formation of a pharmaceutical composition, i.e., adosage form capable of administration to the patient. One example ofsuch a carrier is pharmaceutically acceptable oil typically used forparenteral administration.

The term “pharmaceutically acceptable salts” as used herein means thatthe salts of the compounds of the present invention can be used inmedicinal preparations. Other salts may, however, be useful in thepreparation of the compounds according to the invention or of theirpharmaceutically acceptable salts. Suitable pharmaceutically acceptablesalts of the compounds of this invention include acid addition saltswhich may, for example, be formed by mixing a solution of the compoundaccording to the invention with a solution of a pharmaceuticallyacceptable acid such as hydrochloric acid, hydrobromic acid, nitricacid, sulfamic acid, sulfuric acid, methanesulfonic acid,2-hydroxyethanesulfonic acid, p-toluenesulfonic acid, fumaric acid,maleic acid, hydroxymaleic acid, malic acid, ascorbic acid, succinicacid, glutaric acid, acetic acid, propionic acid, salicylic acid,cinnamic acid, 2-phenoxybenzoic acid, hydroxybenzoic acid, phenylaceticacid, benzoic acid, oxalic acid, citric acid, tartaric acid, glycolicacid, lactic acid, pyruvic acid, malonic acid, carbonic acid orphosphoric acid. The acid metal salts such as sodium monohydrogenorthophosphate and potassium hydrogen sulfate can also be formed. Also,the salts so formed may present either as mono- or di-acid salts and canexist substantially anhydrous or can be hydrated. Furthermore, where thecompounds of the invention carry an acidic moiety, suitablepharmaceutically acceptable salts thereof may include alkali metalsalts, e.g. sodium or potassium salts; alkaline earth metal salts, e.g.calcium or magnesium salts, and salts formed with suitable organicligands, e.g. quaternary ammonium salts.

As used herein, the term “prodrug” shall have the generally acceptedmeaning in the art. One such definition includes a pharmacologicallyinactive chemical entity that when metabolized or chemically transformedby a biological system such as a mammalian system is converted into apharmacologically active substance.

The expression “stereoisomers” is a general term used for all isomers ofthe individual molecules that differ only in the orientation of theiratoms in space. Typically it includes mirror image isomers that areusually formed due to at least one asymmetric center, (enantiomers).Where the compounds according to the invention possess two or moreasymmetric centers, they may additionally exist as diastereoisomers,also certain individual molecules may exist as geometric isomers(cis/trans). Similarly, certain compounds of this invention may exist ina mixture of two or more structurally distinct forms that are in rapidequilibrium, commonly known as tautomers. Representative examples oftautomers include keto-enol tautomers, phenol-keto tautomers,nitroso-oxime tautomers, imine-enamine tautomers, etc. It is to beunderstood that all such isomers and mixtures thereof in any proportionare encompassed within the scope of the present invention. As usedherein, ‘R’ and ‘S’ are used as commonly used terms in organic chemistryto denote specific configuration of a chiral center. The term ‘R’(rectus) refers to that configuration of a chiral center with aclockwise relationship of group priorities (highest to second lowest)when viewed along the bond toward the lowest priority group. The term‘S’ (sinister) refers to that configuration of a chiral center with acounterclockwise relationship of group priorities (highest to secondlowest) when viewed along the bond toward the lowest priority group. Thepriority of groups is based upon sequence rules wherein prioritizationis first based on atomic number (in order of decreasing atomic number).A listing and discussion of priorities is contained in Stereochemistryof Organic Compounds, Ernest L. Eliel, Samuel H. Wilen and Lewis N.Mander, editors, Wiley-Interscience, John Wiley & Sons, Inc., New York,1994.

In addition to the (R) —(S) system, the older D-L system may also beused herein to denote absolute configuration, especially with referenceto amino acids. In this system a Fischer projection formula is orientedso that the number 1 carbon of the main chain is at the top. The prefix‘D’ is used to represent the absolute configuration of the isomer inwhich the functional (determining) group is on the right side of thecarbon at the chiral center and ‘L’, that of the isomer in which it ison the left.

The term “solvate” as used herein means that an aggregate that consistsof a solute ion or molecule with one or more solvent molecules.Similarly, a “hydrate” means that a solute ion or molecule with one ormore water molecules.

In a broad sense, the term “substituted” is contemplated to include allpermissible substituents of organic compounds. In a few of the specificembodiments as disclosed herein, the term “substituted” meanssubstituted with one or more substituents independently selected fromthe group consisting of (C₁-C₆)alkyl, (C₂-C₆)alkenyl,(C₁-C₆)perfluoroalkyl, phenyl, hydroxy, —CO₂H, an ester, an amide,(C₁-C₆)alkoxy, (C₁-C₆)thioalkyl, (C₁-C₆)perfluoroalkoxy, —NH₂, Cl, Br,I, F, —NH-lower alkyl, and —N(lower alkyl)₂. However, any of the othersuitable substituents known to one skilled in the art can also be usedin these embodiments.

“Therapeutically effective amount” means an amount of the compound whichis effective in treating the named disease, disorder or condition.

The term “treating” refers to:

(i) preventing a disease, disorder or condition from occurring in apatient that may be predisposed to the disease, disorder and/orcondition, but has not yet been diagnosed as having it;

(ii) inhibiting the disease, disorder or condition, i.e., arresting itsdevelopment; and

(iii) relieving the disease, disorder or condition, i.e., causingregression of the disease, disorder and/or condition.

Thus, in accordance with the practice of this invention there isprovided a compound of the formula I:

wherein

-   R, R₁, R₂ and R₃ are the same or different and independently of each    other chosen from hydrogen, (C₁-C₄)alkyl or CF₃;-   R₄ is selected from the group consisting of phenyl, cyclohexyl,    pyridinyl, furanyl, isoxazolyl, quinolinyl, naphthyridinyl, indolyl,    benzoimidazolyl, benzofuranyl, chromanyl, 4-oxo-4H-chromenyl,    2,3-dihydro-benzofuranyl, benzo[1,3]dioxolyl and    2,5-dioxo-2,3,4,5-tetrahydro-1H-benzo[e][1,4]diazepinyl; wherein    said R₄ is optionally substituted one or more times with a    substituent selected from halogen, hydroxy, (C₁-C₄)alkyl,    (C₁-C₄)alkoxy, CF₃, hydroxymethyl, 2-hydroxyethylamino,    methoxyethylamide, benzyloxymethyl, piperidinyl,    N-acetyl-piperidinyl, pyrrolyl, imidazolyl and    5-oxo-4,5-dihydro-pyrazolyl.

This invention further includes various salts of the compounds offormula (I) including various enantiomers or diastereomers of compoundsof formula (I). As noted hereinabove and by way of specific exampleshereafter all of the salts that can be formed including pharmaceuticallyacceptable salts are part of this invention. As also noted hereinaboveand hereafter all of the conceivable enantiomeric and diastereomericforms of compounds of formula (I) are part of this invention.

In one of the embodiments, there are disclosed compounds of formula (I)of this invention wherein R and R₂ are methyl; and R₁ and R₃ arehydrogen.

In another embodiment of this invention there is disclosed compounds offormula (I), wherein R₄ is phenyl, wherein phenyl is optionallysubstituted with one or more groups selected from fluorine, methyl,hydroxymethyl, N-acetyl-piperidinyl, imidazolyl or5-oxo-4,5-dihydro-pyrazolyl.

In yet another embodiment of this invention there is disclosed compoundsof formula (I), wherein R₄ is pyridinyl which is optionally substitutedone or more times with chlorine, 2-hydroxyethylamino, methoxyethylamide,benzyloxymethyl or pyrrolyl.

In a further embodiment of this invention there is also disclosedcompounds of formula (I), wherein R₄ is quinolinyl, naphthyridinyl,indolyl, benzoimidazolyl or benzofuranyl, and wherein said R₄ isoptionally substituted one or more times with chlorine, hydroxy, methylor methoxy.

In another embodiment of this invention there is disclosed compounds offormula (I), wherein R₄ is chromanyl, 4-oxo-4H-chromenyl or2,3-dihydro-benzofuranyl, wherein said R₄ is optionally substituted oneor more times with hydroxy or methyl.

In another embodiment of this invention the compound of formula (I),wherein R₄ is benzo[1,3]dioxolyl or2,5-dioxo-2,3,4,5-tetrahydro-1H-benzo[e][1,4]diazepinyl is alsodisclosed.

In an embodiment of this invention specific compounds of formula (I)without any limitation are selected from the group consisting of:

-   (2S,3R)-3-fluoro-N-{2-methyl-4-[3-(2-methyl-pyrrolidin-1-yl-methyl)-pyrrolidin-1-yl]-phenyl}-benzamide;-   (2S,3R)-5-fluoro-2-methyl-N-{2-methyl-4-[3-(2-methyl-pyrrolidin-1-yl-methyl)-pyrrolidin-1-yl]-phenyl}-benzamide;-   4-hydroxymethyl-N-{2-methyl-4-[3-(2-methyl-pyrrolidin-1-ylmethyl)-pyrrolidin-1-yl]-phenyl}-benzamide;-   4-imidazol-1-yl-N-{2-methyl-4-[3-(2-methyl-pyrrolidin-1-ylmethyl)-pyrrolidin-1-yl]-phenyl}-benzamide;-   4-(1-acetyl-piperidin-3-yl)-N-{2-methyl-4-[3-(2-methyl-pyrrolidin-1-ylmethyl)-pyrrolidin-1-yl]-phenyl}-benzamide;-   N-{2-methyl-4-[3-(2-methyl-pyrrolidin-1-ylmethyl)-pyrrolidin-1-yl]-phenyl}-4-(3-methyl-5-oxo-4,5-dihydro-pyrazol-1-yl)-benzamide;-   (2S,3R)-cyclohexanecarboxylic acid    {2-methyl-4-[3-(2-methyl-pyrrolidin-1-yl-methyl)-pyrrolidin-1-yl]-phenyl}-amide;-   5-chloro-6-(2-hydroxy-ethylamino)-N-{2-methyl-4-[3-(2-methyl-pyrrolidin-1-ylmethyl)-pyrrolidin-1-yl]-phenyl}-nicotinamide;-   pyridine-2,5-dicarboxylic acid    2-[(2-methoxy-ethyl)-amide]5-({2-methyl-4-[3-(2-methyl-pyrrolidin-1-ylmethyl)-pyrrolidin-1-yl]-phenyl}-amide);-   N-{2-methyl-4-[3-(2-methyl-pyrrolidin-1-ylmethyl)-pyrrolidin-1-yl]-phenyl}-6-pyrrol-1-yl-nicotinamide;-   6-benzyloxymethyl-N-{2-methyl-4-[3-(2-methyl-pyrrolidin-1-ylmethyl)-pyrrolidin-1-yl]-phenyl}-nicotinamide;-   (2S,3R)-furan-3-carboxylic acid    {2-methyl-4-[3-(2-methyl-pyrrolidin-1-yl-methyl)-pyrrolidin-1-yl]-phenyl}-amide;-   (2S,3R)-3,5-dimethyl-isoxazole-4-carboxylic acid    {2-methyl-4-[3-(2-methyl-pyrrolidin-1-yl-methyl)-pyrrolidin-1-yl]-phenyl}-amide;-   7-chloro-4-hydroxy-quinoline-3-carboxylic acid    {2-methyl-4-[3-(2-methyl-pyrrolidin-1-ylmethyl)-pyrrolidin-1-yl]-phenyl}-amide;-   4-hydroxy-7-methyl-[1,8]naphthyridine-3-carboxylic acid    {2-methyl-4-[3-(2-methyl-pyrrolidin-1-ylmethyl)-pyrrolidin-1-yl]-phenyl}-amide;-   1H-indole-6-carboxylic acid    {2-methyl-4-[3-(2-methyl-pyrrolidin-1-ylmethyl)-pyrrolidin-1-yl]-phenyl}-amide;-   5-methoxy-1H-indole-2-carboxylic acid    {2-methyl-4-[3-(2-methyl-pyrrolidin-1-ylmethyl)-pyrrolidin-1-yl]-phenyl}-amide;-   2-methyl-1H-benzoimidazole-5-carboxylic acid    {2-methyl-4-[3-(2-methyl-pyrrolidin-1-ylmethyl)-pyrrolidin-1-yl]-phenyl}-amide;-   6-methoxy-benzofuran-2-carboxylic acid    {2-methyl-4-[3-(2-methyl-pyrrolidin-1-ylmethyl)-pyrrolidin-1-yl]-phenyl}-amide;-   3,4-dihydroxy-2,2-dimethyl-chroman-6-carboxylic acid    {2-methyl-4-[3-(2-methyl-pyrrolidin-1-ylmethyl)-pyrrolidin-1-yl]-phenyl}-amide;-   6-methyl-4-oxo-4H-chromene-2-carboxylic acid    {2-methyl-4-[3-(2-methyl-pyrrolidin-1-ylmethyl)-pyrrolidin-1-yl]-phenyl}-amide;-   2,3-dihydro-benzofuran-5-carboxylic acid    {2-methyl-4-[3-(2-methyl-pyrrolidin-1-ylmethyl)-pyrrolidin-1-yl]-phenyl}-amide;-   benzo[1,3]dioxole-5-carboxylic acid    {2-methyl-4-[3-(2-methyl-pyrrolidin-1-ylmethyl)-pyrrolidin-1-yl]-phenyl}-amide;    and-   2,5-dioxo-2,3,4,5-tetrahydro-1H-benzo[e][1,4]diazepine-8-carboxylic    acid    {2-methyl-4-[3-(2-methyl-pyrrolidin-1-ylmethyl)-pyrrolidin-1-yl]-phenyl}-amide.

All of the above compounds may also include corresponding salts whereverpossible including the pharmaceutically acceptable salts thereof.

In another aspect of this invention the following compounds encompassedby compound of formula (I) of this invention without any limitation maybe enumerated:

-   (2S,3R)-3-fluoro-N-{2-methyl-4-[3-(2-methyl-pyrrolidin-1-yl-methyl)-pyrrolidin-1-yl]-phenyl}-benzamide-   (2S,3R)-5-fluoro-2-methyl-N-{2-methyl-4-[3-(2-methyl-pyrrolidin-1-yl-methyl)-pyrrolidin-1-yl]-phenyl}-benzamide;-   4-hydroxymethyl-N-{2-methyl-4-[3-(2-methyl-pyrrolidin-1-ylmethyl)-pyrrolidin-1-yl]-phenyl}-benzamide;-   4-imidazol-1-yl-N-{2-methyl-4-[3-(2-methyl-pyrrolidin-1-ylmethyl)-pyrrolidin-1-yl]-phenyl}-benzamide;-   4-(1-acetyl-piperidin-3-yl)-N-{2-methyl-4-[3-(2-methyl-pyrrolidin-1-ylmethyl)-pyrrolidin-1-yl]-phenyl}-benzamide;-   N-{2-methyl-4-[3-(2-methyl-pyrrolidin-1-ylmethyl)-pyrrolidin-1-yl]-phenyl}-4-(3-methyl-5-oxo-4,5-dihydro-pyrazol-1-yl)-benzamide;-   (2S,3R)-cyclohexanecarboxylic acid    {2-methyl-4-[3-(2-methyl-pyrrolidin-1-yl-methyl)-pyrrolidin-1-yl]-phenyl}-amide;-   5-chloro-6-(2-hydroxy-ethylamino)-N-{2-methyl-4-[3-(2-methyl-pyrrolidin-1-ylmethyl)-pyrrolidin-1-yl]-phenyl}-nicotinamide;-   pyridine-2,5-dicarboxylic acid    2-[(2-methoxy-ethyl)-amide]5-({2-methyl-4-[3-(2-methyl-pyrrolidin-1-ylmethyl)-pyrrolidin-1-yl]-phenyl}-amide);-   N-{2-methyl-4-[3-(2-methyl-pyrrolidin-1-ylmethyl)-pyrrolidin-1-yl]-phenyl}-6-pyrrol-1-yl-nicotinamide;-   6-benzyloxymethyl-N-{2-methyl-4-[3-(2-methyl-pyrrolidin-1-ylmethyl)-pyrrolidin-1-yl]-phenyl}-nicotinamide;-   (2S,3R)-furan-3-carboxylic acid    {2-methyl-4-[3-(2-methyl-pyrrolidin-1-yl-methyl)-pyrrolidin-1-yl]-phenyl}-amide;-   (2S,3R)-3,5-dimethyl-isoxazole-4-carboxylic acid    {2-methyl-4-[3-(2-methyl-pyrrolidin-1-yl-methyl)-pyrrolidin-1-yl]-phenyl}-amide;-   7-chloro-4-hydroxy-quinoline-3-carboxylic acid    {2-methyl-4-[3-(2-methyl-pyrrolidin-1-ylmethyl)-pyrrolidin-1-yl]-phenyl}-amide;-   4-hydroxy-7-methyl-[1,8]naphthyridine-3-carboxylic acid    {2-methyl-4-[3-(2-methyl-pyrrolidin-1-ylmethyl)-pyrrolidin-1-yl]-phenyl}-amide;-   1H-indole-6-carboxylic acid    {2-methyl-4-[3-(2-methyl-pyrrolidin-1-ylmethyl)-pyrrolidin-1-yl]-phenyl}-amide;-   5-methoxy-1H-indole-2-carboxylic acid    {2-methyl-4-[3-(2-methyl-pyrrolidin-1-ylmethyl)-pyrrolidin-1-yl]-phenyl}-amide;    and-   2-methyl-1H-benzoimidazole-5-carboxylic acid    {2-methyl-4-[3-(2-methyl-pyrrolidin-1-ylmethyl)-pyrrolidin-1-yl]-phenyl}-amide;

Again all of the conceivable salts of the above noted compoundsincluding the pharmaceutically acceptable salts are part of thisinvention.

In a further aspect of this invention the following compounds within thescope of this invention may be enumerated:

-   (2S,3R)-3-fluoro-N-{2-methyl-4-[3-(2-methyl-pyrrolidin-1-yl-methyl)-pyrrolidin-1-yl]-phenyl}-benzamide-   (2S,3R)-5-fluoro-2-methyl-N-{2-methyl-4-[3-(2-methyl-pyrrolidin-1-yl-methyl)-pyrrolidin-1-yl]-phenyl}-benzamide;-   4-hydroxymethyl-N-{2-methyl-4-[3-(2-methyl-pyrrolidin-1-ylmethyl)-pyrrolidin-1-yl]-phenyl}-benzamide;-   4-imidazol-1-yl-N-{2-methyl-4-[3-(2-methyl-pyrrolidin-1-ylmethyl)-pyrrolidin-1-yl]-phenyl}-benzamide;-   4-(1-acetyl-piperidin-3-yl)-N-{2-methyl-4-[3-(2-methyl-pyrrolidin-1-ylmethyl)-pyrrolidin-1-yl]-phenyl}-benzamide;-   N-{2-methyl-4-[3-(2-methyl-pyrrolidin-1-ylmethyl)-pyrrolidin-1-yl]-phenyl}-4-(3-methyl-5-oxo-4,5-dihydro-pyrazol-1-yl)-benzamide;-   5-chloro-6-(2-hydroxy-ethylamino)-N-{2-methyl-4-[3-(2-methyl-pyrrolidin-1-ylmethyl)-pyrrolidin-1-yl]-phenyl}-nicotinamide;-   pyridine-2,5-dicarboxylic acid    2-[(2-methoxy-ethyl)-amide]5-({2-methyl-4-[3-(2-methyl-pyrrolidin-1-ylmethyl)-pyrrolidin-1-yl]-phenyl}-amide);-   N-{2-methyl-4-[3-(2-methyl-pyrrolidin-1-ylmethyl)-pyrrolidin-1-yl]-phenyl}-6-pyrrol-1-yl-nicotinamide;    and-   6-b    enzyloxymethyl-N-{2-methyl-4-[3-(2-methyl-pyrrolidin-1-ylmethyl)-pyrrolidin-1-yl]-phenyl}-nicotinamide;

Again all of the conceivable salts of the above noted compoundsincluding the pharmaceutically acceptable salts are part of thisinvention.

In another aspect of this invention the compound of this invention maybe represented by a specific stereoisomeric form of formula (II):

wherein R, R₁, R₂, R₃ and R₄ are as defined hereinabove.

The compounds of this invention can be synthesized by any of theprocedures known to one skilled in the art. Specifically, several of thestarting materials used in the preparation of the compounds of thisinvention are known or are themselves commercially available. Thecompounds of this invention and several of the precursor compounds mayalso be prepared by methods used to prepare similar compounds asreported in the literature and as further described herein. Forinstance, as stated hereinabove a few of the structurally similarcompounds have been disclosed in U.S. Pat. No. 7,223,788. Also, see R.C. Larock, “Comprehensive Organic Transformations,” VCH publishers,1989.

It is also well known that in various organic reactions it may benecessary to protect reactive functional groups, such as for example,amino groups, to avoid their unwanted participation in the reactions.Conventional protecting groups may be used in accordance with standardpractice and known to one of skilled in the art, for example, see T. W.Greene and P. G. M. Wuts in “Protective Groups in Organic Chemistry”John Wiley and Sons, Inc., 1991. For example, suitable amine protectinggroups include without any limitation sulfonyl (e.g., tosyl), acyl(e.g., benzyloxycarbonyl or t-butoxycarbonyl) and arylalkyl (e.g.,benzyl), which may be removed subsequently by hydrolysis orhydrogenation as appropriate. Other suitable amine protecting groupsinclude trifluoroacetyl [—C(═O)CF₃] which may be removed by basecatalyzed hydrolysis, or a solid phase resin bound benzyl group, such asa Merrifield resin bound 2,6-dimethoxybenzyl group (Ellman linker) or a2,6-dimethoxy-4-[2-(polystyrylmethoxy)ethoxy]benzyl, which may beremoved by acid catalyzed hydrolysis, for example with TFA.

More specifically, the compounds disclosed herein and various precursorsused therefor can be synthesized according to the following proceduresof Schemes 1-3, wherein R, R₁, R₂, R₃ and R₄ are as defined for FormulaI unless otherwise indicated.

For instance, Scheme 1 illustrates the preparation of the intermediate(8), which is prepared in accordance with the procedures disclosed inBioorg. Med. Chem. 2004, 12 (10), 2603.

In Scheme 1, step 1, α-amino-acetic acid (2) is condensed with butylacrylate (1) in the presence of formaldehyde to formpyrrolidine-3-carboxylic acid butyl ester (3). This reaction cannormally be carried out in a suitable organic solvent such as tolueneunder reflux temperature conditions. However, various other suitableconditions that are known to one skilled in the art can also beemployed.

In Scheme 1, step 2, the nitrogen atom of intermediate (3) is suitablyprotected, for example, by reacting with t-butyl carbonic acid anhydrideso as to protect nitrogen by t-butyloxycarbonyl group to formintermediate (4). Such reactions can again be performed using any of theprocedures known to one skilled in the art. It should also be understoodthat any of the other known protecting groups can be employed to achievethe same results, i.e., to form a suitably protected intermediate (4).

In Scheme 1, step 3, the intermediate (4) is further reacted with asuitable reagent such as for example a base like lithium hydroxide in asuitable solvent such as methanol to form carboxylic acid intermediate(5). Such ester hydrolysis can also be carried out under acidicconditions and/or essentially neutral conditions using various knownacids and/or acidic agents as well as silyl compounds which are wellknown to one of skilled in the art.

In Scheme 1, step 4, the acid intermediate (5) is reacted with asubstituted pyrrolidine of formula (6), wherein R is as defined herein.Such coupling reaction can be carried out in the presence of reagentssuch as a combination of N-methylmorpholine, 1-hydroxybenzotraizole andEDC hydrochloride in the presence of a suitable organic solvent such asdichloromethane. However, any of the other methods that will bring aboutthis transformation can also be employed herein.

In Scheme 1, step 5, the intermediate (7) is deprotected to formintermediate (8), for example using hydrochloric acid in the presence ofa suitable solvent such as methanol. Again, any of the other known acidand/or basic reagents that would deprotect the nitrogen can be employedin this step.

Finally, in Scheme 1, step 6, the intermediate (8) is subjectedreductive conditions to form the desired intermediate (9). Various knownreduction methods to convert a carbonyl to methylene group can beemployed in this step. For example, intermediate (8) is subjected toreductive conditions in the presence of lithium aluminum hydride in anorganic solvent such as tetrahydrofuran to form intermediate (9).

Similarly, an enantiomerically pure form of intermediate (9) can beformed using the appropriate starting materials in accordance with theprocedures set forth in Scheme 1. Specific examples of enantiomericallyenriched compounds of this invention are illustrated below.

Scheme 2 illustrates the preparation ofamino-phenyl-pyrrolidinyl-methylpyrrolidine intermediate of formula(12), wherein R, R₁ and R₂ are as defined herein.

In Scheme 2, step 1, suitably substituted nitrobenzene of formula (10),wherein X is a suitable leaving group, such as Cl, F, Br, or triflate(OTf) is condensed with the [1,3′]-pyrrolidinyl-methylpyrrolidine offormula (9) in order to form an intermediate of formula (11). Suchcondensation reactions can again be carried out using any of theprocedures known to one skilled in the art. For example, suchcondensation reaction can be carried out in a polar solvent such as DMSOin the presence of a base such as potassium carbonate at ambient tosuper-ambient temperature conditions.

In Scheme 2, step 2, intermediate of formula (II) is reduced byhydrogenation or other known chemical methods, such as using tindichloride in hydrochloric acid, to form the key intermediate (12).

Scheme 3 illustrates the preparation of compounds of formula (I) of thisinvention using either Method A or Method B depending upon theavailability of desired carboxylic acid of formula R₄—CO₂H either in theform of acid itself or its acid chloride, wherein R, R₁, R₂ and R₄ areas described herein and R₃ is hydrogen.

In Method A, Scheme 3 the acid chloride of formula (13) can be reactedwith the intermediate (12) using any of the conditions known to oneskilled in the art. Typically, such conditions include without anylimitations reaction of the acid chloride with the intermediate offormula (12) in a suitable organic solvent such as for exampledichloromethane in the presence of a suitable base such as pyridine.Such reactions are generally carried out at sub-ambient temperatureconditions, for example around 0° C., however ambient to super-ambienttemperature conditions may also be suitable in certain situationsdepending upon the nature of the acid chloride and the intermediate(12).

Similarly, in Method B, Scheme 3, the carboxylic acid of formula (14)can be reacted with the intermediate of formula (12) under variousreaction conditions known to one skilled in the art. For instance, theacid of formula (14) is reacted with intermediate of formula (12) atsub-ambient temperature conditions in the presence of suitable reagentssuch as for example a mixture of N-methylmorpholine,1-hydroxybenzotriazole and EDC.

As already noted hereinabove, the compounds of this invention canreadily be converted into salts. More particularly, the compounds of thepresent invention are basic, and as such compounds of this invention areuseful in the form of the free base or in the form of a pharmaceuticallyacceptable acid addition salt thereof. Acid addition salts may be a moreconvenient form for use; and, in practice, use of the salt forminherently amounts to use of the free base form. The acids which can beused to prepare the acid addition salts include preferably those whichproduce, when combined with the free base, pharmaceutically acceptablesalts, that is, salts whose anions are non-toxic to the patient inpharmaceutical doses of the salts, so that the beneficial inhibitoryeffects inherent in the free base are not vitiated by side effectsascribable to the anions. Although pharmaceutically acceptable salts ofsaid basic compound is preferred, all acid addition salts are useful assources of the free base form even if the particular salt, per se, isdesired only as an intermediate product as, for example, when the saltis formed only for purposes of purification, and identification, or whenit is used as intermediate in preparing a pharmaceutically acceptablesalt by ion exchange procedures.

In another aspect of this embodiment, a specific disease, a disorder ora condition that can be treated with the compound of this inventioninclude, without any limitation the following: sleep-related disorders(specific examples include without any limitation narcolepsy, circadianrhythm sleep disorders, obstructive sleep apnea, periodic limb movementand restless leg syndrome, excessive sleepiness and drowsiness due tomedication side-effect, etc.), neurological disorders (specific examplesthat may be enumerated include but not limited to dementia, Alzheimer'sdisease, multiple sclerosis, epilepsy and neuropathic pain),neuropsychological and cognitive disorders (a few of the specificexamples include without any limitation include schizophrenia, attentiondeficit/hyperactivity disorder, Alzheimer's disease, depression,seasonal affective disorder, and cognitive impairment).

As described hereinbelow by way of specific examples, the compounds offormula (I) bind to the H3 receptors and demonstrate inverse agonismversus H3 functional activity. Therefore, the compounds of thisinvention may have utility in the treatment of diseases or conditionsameliorated with H3 receptor ligands. More specifically, the compoundsof the present invention are H3 receptor ligands that modulate functionof the H3 receptor by antagonizing the activity of the receptor.Further, the compounds of this invention may be inverse agonists thatinhibit the basal activity of the receptor or they may be antagoniststhat completely block the action of receptor-activating agonists.Additionally, the compounds of this invention may also be partialagonists that partially block or partially activate the H3 receptor orthey may be agonists that activate the receptor. Thus the compounds ofthis invention may act differentially as antagonists, inverse agonistsand/or partial agonists depending on functional output, histamine toneand or tissue context. Accordingly, the differential activities of thesecompounds may allow for utility to ameliorate multiple disease states asspecifically enumerated above.

Thus in one aspect of this invention there is provided a method oftreating a disease in a patient, said disease selected from the groupconsisting of sleep related disorder, dementia, Alzheimer's disease,multiple sclerosis, cognitive disorder, attention deficit hyperactivitydisorder and depression, comprising administering to said patient atherapeutically effective amount of a compound of formula (I).

One of skill in the art readily appreciates that the pathologies anddisease states expressly stated herein are not intended to be limitingrather to illustrate the efficacy of the compounds of the presentinvention. Thus it is to be understood that the compounds of thisinvention may be used to treat any disease caused by the effects of H3receptors. That is, as noted above, the compounds of the presentinvention are modulators of H3 receptors and may be effectivelyadministered to ameliorate any disease state which is mediated all or inpart by H3 receptors.

All of the various embodiments of the compounds of this invention asdisclosed herein can be used in the method of treating various diseasestates as described herein. As stated herein, the compounds used in themethod of this invention are capable of inhibiting the effects of H3receptor and thereby alleviating the effects and/or conditions causeddue to the activity of H3.

In another embodiment of the method of this invention, the compounds ofthis invention can be administered by any of the methods known in theart. Specifically, the compounds of this invention can be administeredby oral, intramuscular, subcutaneous, rectal, intratracheal, intranasal,intraperitoneal or topical route.

Finally, in yet another embodiment of this invention, there is alsoprovided a pharmaceutical composition comprising a pharmaceuticallyacceptable carrier and a compound of formula (I), including enantiomers,stereoisomers, and tautomers of said compound and pharmaceuticallyacceptable salts, solvates or derivatives thereof, with said compoundhaving the general structure shown in formula I as described herein.

As described herein, the pharmaceutical compositions of this inventionfeature H3 inhibitory activity and thus are useful in treating anydisease, condition or a disorder caused due to the effects of H3 in apatient. Again, as described above, all of the preferred embodiments ofthe compounds of this invention as disclosed herein can be used inpreparing the pharmaceutical compositions as described herein.

Preferably the pharmaceutical compositions of this invention are in unitdosage forms such as tablets, pills, capsules, powders, granules,sterile parenteral solutions or suspensions, metered aerosol or liquidsprays, drops, ampoules, auto-injector devices or suppositories; fororal, parenteral, intranasal, sublingual or rectal administration, orfor administration by inhalation or insufflation. Alternatively, thecompositions may be presented in a form suitable for once-weekly oronce-monthly administration; for example, an insoluble salt of theactive compound, such as the decanoate salt, may be adapted to provide adepot preparation for intramuscular injection. An erodible polymercontaining the active ingredient may be envisaged. For preparing solidcompositions such as tablets, the principal active ingredient is mixedwith a pharmaceutical carrier, e.g. conventional tableting ingredientssuch as corn starch, lactose, sucrose, sorbitol, talc, stearic acid,magnesium stearate, dicalcium phosphate or gums, and otherpharmaceutical diluents, e.g. water, to form a solid preformulationcomposition containing a homogeneous mixture of a compound of thepresent invention, or a pharmaceutically acceptable salt thereof. Whenreferring to these preformulation compositions as homogeneous, it ismeant that the active ingredient is dispersed evenly throughout thecomposition so that the composition may be readily subdivided intoequally effective unit dosage forms such as tablets, pills and capsules.This solid preformulation composition is then subdivided into unitdosage forms of the type described above containing from 0.1 to about500 mg of the active ingredient of the present invention. Flavored unitdosage forms contain from 1 to 100 mg, for example 1, 2, 5, 10, 25, 50or 100 mg, of the active ingredient. The tablets or pills of the novelcomposition can be coated or otherwise compounded to provide a dosageform affording the advantage of prolonged action. For example, thetablet or pill can comprise an inner dosage and an outer dosagecomponent, the latter being in the form of an envelope over the former.The two components can be separated by an enteric layer which serves toresist disintegration in the stomach and permits the inner component topass intact into the duodenum or to be delayed in release. A variety ofmaterials can be used for such enteric layers or coatings, suchmaterials including a number of polymeric acids and mixtures ofpolymeric acids with such materials as shellac, cetyl alcohol andcellulose acetate.

The liquid forms in which the novel compositions of the presentinvention may be incorporated for administration orally or by injectioninclude aqueous solutions, suitably flavored syrups, aqueous or oilsuspensions, and flavored emulsions with edible oils such as cottonseedoil, sesame oil, coconut oil or peanut oil, as well as elixirs andsimilar pharmaceutical vehicles. Suitable dispersing or suspendingagents for aqueous suspensions include synthetic and natural gums suchas tragacanth, acacia, alginate, dextran, sodium carboxymethylcellulose,methylcellulose, polyvinyl-pyrrolidone or gelatin.

The pharmaceutical compositions of this invention can be administered byany of the methods known in the art. In general, the pharmaceuticalcompositions of this invention can be administered by oral,intramuscular, subcutaneous, rectal, intratracheal, intranasal,intraperitoneal or topical route. The preferred administrations of thepharmaceutical composition of this invention are by oral and intranasalroutes. Any of the known methods to administer pharmaceuticalcompositions by an oral or an intranasal route can be used to administerthe composition of this invention.

In the treatment of various disease states as described herein, asuitable dosage level is about 0.01 to 250 mg/kg per day, preferablyabout 0.05 to 100 mg/kg per day, and especially about 0.05 to 20 mg/kgper day. The compounds may be administered on a regimen of 1 to 4 timesper day.

This invention is further illustrated by the following examples whichare provided for illustration purposes and in no way limit the scope ofthe present invention.

EXAMPLES General

Reactions generally are run under a nitrogen atmosphere. Solvents aredried over magnesium sulfate and are evaporated under vacuum on a rotaryevaporator. TLC analyses are performed with EM Science silica gel 60F254 plates with visualization by UV irradiation. Flash chromatographyis performed using Alltech prepacked silica gel cartridges. The ¹H NMRspectra are run at 300 MHz on a Gemini 300 or Varian VXR 300spectrometer and are determined in a deuterated solvent, such as DMSO-D₆or CDCl₃ unless otherwise noted. Chemical shifts values are indicated inparts per million (ppm) with reference to tetramethylsilane (TMS) as theinternal standard. The LC/MS are run on a Micromass Platform LCZ.

As used in the examples and preparations that follow, the terms usedtherein shall have the meanings indicated: “kg” refers to kilograms, “g”refers to grams, “mg” refers to milligrams, “μg” refers to micrograms,“pg” refers to picograms, “lb” refers to pounds, “oz” refers to ounces,“mol” refers to moles, “mmol” refers to millimoles, “μmole” refers tomicromoles, “nmole” refers to nanomoles, “L” refers to liters, “mL” or“ml” refers to milliliters, “μL” refers to microliters, “gal” refers togallons, “° C.” refers to degrees Celsius, “R_(f)” refers to retentionfactor, “mp” or “m.p.” refers to melting point, “dec” refers todecomposition, “bp” or “b.p.” refers to boiling point, “mm of Hg” refersto pressure in millimeters of mercury, “cm” refers to centimeters, “nm”refers to nanometers, “abs.” refers to absolute, “conc.” refers toconcentrated, “c” refers to concentration in g/mL, “THF” refers totetrahydrofuran, “DMF” refers to dimethylformamide, “NMP” refers to1-methyl-2-pyrrolidinone, “brine” refers to a saturated aqueous sodiumchloride solution, “M” refers to molar, “mM” refers to millimolar, “μM”refers to micromolar, “nM” refers to nanomolar, “N” refers to normal,“TLC” refers to thin layer chromatography, “HPLC” refers to highperformance liquid chromatography, “HRMS” refers to high resolution massspectrum, “L.O.D.” refers to loss on drying, “μCi” refers tomicrocuries, “i.p.” refers to intraperitoneally, “i.v.” refers tointravenously, anhyd=anhydrous; aq=aqueous; min=minute; hr=hour; d=day;sat.=saturated; s=singlet, d=doublet; t=triplet; q=quartet; m=multiplet;dd=doublet of doublets; br=broad; LC=liquid chromatograph; MS=massspectrograph; ESI/MS=electrospray ionization/mass spectrograph;RT=retention time; M=molecular ion.

Intermediate (i)(2S,3S)-3-(2-Methyl-pyrrolidine-1-carbonyl)-pyrrolidine-1-carboxylicacid tert-butyl ester

(3S)-Pyrrolidine-1,3-dicarboxylic acid 1-tert-butyl ester (purchasedfrom Astatech, Inc, 0.5 g, 2.3 mmol) was dissolved in DCM (20 mL) andthe solution was cooled to an ice-water bath. To this solution was addeda solution of (S)-2-methyl-pyrrolidine (purchased from AdvancedAsymmetric, Inc., 235 mg, 2.76 mmol, 1.2 equiv.) in 1 mL of DCM,followed by N-methylmorpholine (700 mg, 6.9 mmol, 3 equiv.) and1-hydroxylbenzotriazole (HOBT) (404 mg, 3 mmol, 1.3 equiv.)sequentially, and finally EDC.HCl (576 mg, 3 mmol, 1.3 equiv.). Theresultant clear light brown solution was stirred at r.t. overnight. TLC(10% MeOH in DCM) and LC/MS detected the product peak at a retentiontime of 3.238 min with MS 227 (M-t-Bu). The reaction was quenched withaqueous saturated sodium bicarbonate solution (10 mL) and 10 mL of DCM.The two layers were separated, and the aqueous layer was extracted withDCM (15 mL×2). The combined DCM extracts were washed successively withsodium bicarbonate (10 mL) and brine (10 mL), dried (anhydrous potassiumcarbonate), filtered, and concentrated in vacuum to obtain the titlecompound, 0.65 g (100% yield), as a thick oil.

LC/MS: Tr=3.238 min; MS: 227 (M-tBu).

¹H NMR (300 MHz, CDCl₃), δ (ppm): 4.40 (m, 1H), 3.95-3.20 (m, 6H),2.65-2.00 (m, 5H), 1.95 (m, 1H), 1.65 (s, 9H), 1.35 (m, 2H).

Intermediate (ii) (2S,3S) (2-Methyl-pyrrolidin-1-yl)-pyrrolidin-3-yl-methanone

(2S,3S)-3-(2-Methyl-pyrrolidine-1-carbonyl)-pyrrolidine-1-carboxylicacid tert-butyl ester, as obtained above (˜2.3 mmol) was treated with 3mL of 4M HCl in dioxane at a temperature in the range of 0° C. to rt.overnight. LC/MS detected a product peak at t=1.219 with MS of 183. Nostarting material peak was detected. The excess reagent was removed byblowing dry nitrogen through the reaction mixture which passed thoughpotassium hydroxide column to absorb hydrogen chloride for 1 h. Thesolvent was removed by evaporation under high vacuum. The residue wasfurther dried under high vacuum for 2 h to obtain the title compound asa semi-solid, 0.85 g, as a hydrochloride salt with unspecified number ofhydration. LC/MS: T=1.219 min, MS: 183 (M+H).

Intermediate (iii) (2S,3S)-2-Methyl-1-pyrrolidin-3-ylmethyl-pyrrolidine

To a solution of(2S,3S)-(2-Methyl-pyrrolidin-1-yl)-pyrrolidin-3-yl-methanone (2.3 mmol,as obtained above) in dry THF (6 mL) was added drop-wise 2 M solution ofBH₃SMe₂ in THF (2M in THF, 5 mL, 10 mmol, 4 equiv.). The mixture wasrefluxed for 2 h. The solution was cooled to rt, 5 mL of methanol wasadded and stirred for 2 h at r.t. The solvent was evaporated to drynessto obtain 0.46 g of the title product as a semi-solid. LC/MS showed themolecular ion peak of the title compound at 169 (M+H) with a retentiontime of 1.742 min.

Intermediate (iv)(2S,3R)-2-Methyl-1-[1-(3-methyl-4-nitro-phenyl)-pyrrolidin-3-ylmethyl]-pyrrolidine

(2S,3S)-2-Methyl-1-pyrrolidin-3-ylmethyl-pyrrolidine (2 mmol) wasdissolved in anhydrous DMSO (10 mL). To this solution was added5-fluoro-2-nitrotoluene (620 mg, 4 mmol, 2 equiv.), followed by powderedpotassium carbonate (1.1 g, 8 mmol, 4 equiv.). The suspension was heatedon an oil bath to 85° C. (bath temperature) for 4 h when the startingmaterial was consumed as assayed by LC/MS. MS showed 304 (base).

To this suspension were added 5 mL of water and 10 mL of DCM. The twolayers were separated, and the aqueous layer was extracted with DCM (10mL×2). The combined DCM extracts were successively washed with sodiumbicarbonate (10 mL) and brine (10 mL×2), dried (anhydrous potassiumcarbonate), filtered, and concentrated in vacuo. The crude product waspurified on a silica gel column, eluted with 0-2% MeOH in DCM to obtainthe title compound as a yellow solid after drying. MS: 304 (M+1).

¹H NMR (300 MHz, CDCl₃), δ (ppm): 8.08 (d, 9.2 Hz, 1H), 6.36 (dd, 9.2,2.8 Hz, 1H), 6.28 (d, 2.2 Hz, 1H), 3.6 (m, 1H), 3.4 (m, 2H), 3.20 (m,1H), 3.05 (m, 1H), 2.78 (m, 2H), 2.62 (s, 3H), 2.40-1.60 (m, 8H), 1.45(m, 1H), 1.08 (d, 6.2 Hz, 3H).

Intermediate (v)(2S,3R)-2-Methyl-4-[3-(2-methyl-pyrrolidin-1-ylmethyl)-pyrrolidin-1-yl]-phenylamine

A solution of(2S,3R)-2-methyl-1-[1-(3-methyl-4-nitro-phenyl)-pyrrolidin-3-yl-methyl]-pyrrolidine(0.3 g, 1 mmol) in MeOH (15 mL) was deaerated and nitrogen wasintroduced. To this solution was added Pd—C (10%, 30 mg). This mixturewas stirred under H₂ atmosphere at r.t. overnight. TLC (10% MeOH in DCM)and LC/MS showed the reaction was complete, product peak was observed att=1.458 min, m/z: 274 (M). The mixture was passed through a Celite pad,rinsed with methanol. The filtrate was concentrated to dryness, andfurther dried under high vacuum to yield the title compound as a reddishbrown liquid after drying under high vacuum.

Example 1 2-M ethyl-1H-benzoimidazole-5-carboxylic acid{2-methyl-4-[3-(2-methyl-pyrrolidin-1-ylmethyl)-pyrrolidin-1-yl]-phenyl}-amide

2-Methyl-4-[3-(2-methyl-pyrrolidin-1-ylmethyl)-pyrrolidin-1-yl]-phenylamine(27 mg, 0.1 mmol) and 2-methyl-1H-benzoimidazole-5-carboxylic acid (17.6mg, 0.1 mmol) were dissolved in a mixture of 3 ml of dichloromethane and1 ml of dimethylformamide. To this solution was then addedN-methylmorpholine (33 μl, 0.3 mmol), 1-hydroxybenzotriazole (17.6 mg,0.13 mmol), and 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide (22 mg,0.123 mmol). The reaction was stirred at room temperature for 20 h.Evaporation and RP-HPLC gave 25 mg of the title compound withtrifluoro-acetic acid as a salt (46%). MS: 432.5 (M+H)

Example 25-Chloro-6-(2-hydroxy-ethylamino)-N-{2-methyl-4-[3-(2-methyl-pyrrolidin-1-ylmethyl)-pyrrolidin-1-yl]-phenyl}-nicotinamide

The title compound was prepared in a manner substantially the same asExample 1 by coupling2-methyl-4-[3-(2-methyl-pyrrolidin-1-ylmethyl)-pyrrolidin-1-yl]-phenylaminewith 5-chloro-6-(2-hydroxy-ethylamino)-nicotinic acid. MS: 472.3 (M+H).

Example 3 7-Chloro-4-hydroxy-quinoline-3-carboxylic acid{2-methyl-4-[3-(2-methyl-pyrrolidin-1-ylmethyl)-pyrrolidin-1-yl]-phenyl}-amide

The title compound was prepared in a manner substantially the same asExample 1 by coupling2-methyl-4-[3-(2-methyl-pyrrolidin-1-ylmethyl)-pyrrolidin-1-yl]-phenylaminewith 7-chloro-4-hydroxy-quinoline-3-carboxylic acid. MS: 479.2 (M+H).

Example 4N-{2-Methyl-4-[3-(2-methyl-pyrrolidin-1-ylmethyl)-pyrrolidin-1-yl]-phenyl}-6-pyrrol-1-yl-nicotinamide

The title compound was prepared in a manner substantially the same asExample 1 by coupling2-methyl-4-[3-(2-methyl-pyrrolidin-1-ylmethyl)-pyrrolidin-1-yl]-phenylaminewith 6-pyrrol-1-yl-nicotinic acid. MS: 444.5 (M+H).

Example 5 2,3-Dihydro-benzofuran-5-carboxylic acid{2-methyl-4-[3-(2-methyl-pyrrolidin-1-ylmethyl)-pyrrolidin-1-yl]-phenyl}-amide

The title compound was prepared in a manner substantially the same asExample 1 by coupling2-methyl-4-[3-(2-methyl-pyrrolidin-1-ylmethyl)-pyrrolidin-1-yl]-phenylaminewith 2,3-dihydro-benzofuran-5-carboxylic acid. MS: 420.3 (M+H).

Example 66-Benzyloxymethyl-N-{2-methyl-4-[3-(2-methyl-pyrrolidin-1-ylmethyl)-pyrrolidin-1-yl]-phenyl}-nicotinamide

The title compound was prepared in a manner substantially the same asExample 1 by coupling2-methyl-4-[3-(2-methyl-pyrrolidin-1-ylmethyl)-pyrrolidin-1-yl]-phenylaminewith 6-benzyloxymethyl-nicotinic acid. MS: 499.3 (M+H).

Example 7 Benzo[1,3]dioxole-5-carboxylic acid{2-methyl-4-[3-(2-methyl-pyrrolidin-1-ylmethyl)-pyrrolidin-1-yl]-phenyl}-amide

The title compound was prepared in a manner substantially the same asExample 1 by coupling2-methyl-4-[3-(2-methyl-pyrrolidin-1-ylmethyl)-pyrrolidin-1-yl]-phenylaminewith benzo[1,3]dioxole-5-carboxylic acid. MS: 422.5 (M+H).

Example 8 1H-Indole-6-carboxylic acid{2-methyl-4-[3-(2-methyl-pyrrolidin-1-ylmethyl)-pyrrolidin-1-yl]-phenyl}-amide

The title compound was prepared in a manner substantially the same asExample 1 by coupling2-methyl-4-[3-(2-methyl-pyrrolidin-1-ylmethyl)-pyrrolidin-1-yl]-phenylaminewith 1H-indole-6-carboxylic acid. MS: 417.5 (M+H).

Example 94-Imidazol-1-yl-N-{2-methyl-4-[3-(2-methyl-pyrrolidin-1-ylmethyl)-pyrrolidin-1-yl]-phenyl}-benzamide

The title compound was prepared in a manner substantially the same asExample 1 by coupling2-methyl-4-[3-(2-methyl-pyrrolidin-1-ylmethyl)-pyrrolidin-1-yl]-phenylaminewith 4-imidazol-1-yl-benzoic acid. MS: 444.3 (M+H).

Example 104-(1-Acetyl-piperidin-3-yl)-N-{2-methyl-4-[3-(2-methyl-pyrrolidin-1-ylmethyl)-pyrrolidin-1-yl]-phenyl}-benzamide

The title compound was prepared in a manner substantially the same asExample 1 by coupling2-methyl-4-[3-(2-methyl-pyrrolidin-1-ylmethyl)-pyrrolidin-1-yl]-phenylaminewith 4-(1-acetyl-piperidin-3-yl)-benzoic acid. MS: 503.3 (M+H).

Example 114-Hydroxymethyl-N-{2-methyl-4-[3-(2-methyl-pyrrolidin-1-ylmethyl)-pyrrolidin-1-yl]-phenyl}-benzamide

The title compound was prepared in a manner substantially the same asExample 1 by coupling2-methyl-4-[3-(2-methyl-pyrrolidin-1-ylmethyl)-pyrrolidin-1-yl]-phenylaminewith 4-hydroxymethyl-benzoic acid. MS: 408.5 (M+H).

Example 12 5-Methoxy-1H-indole-2-carboxylic acid{2-methyl-4-[3-(2-methyl-pyrrolidin-1-ylmethyl)-pyrrolidin-1-yl]-phenyl}-amide

The title compound was prepared in a manner substantially the same asExample 1 by coupling2-methyl-4-[3-(2-methyl-pyrrolidin-1-ylmethyl)-pyrrolidin-1-yl]-phenylaminewith 5-methoxy-1H-indole-2-carboxylic acid. MS: 447.5 (M+H).

Example 132,5-Dioxo-2,3,4,5-tetrahydro-1H-benzo[e][1,4]diazepine-8-carboxylic acid{2-methyl-4-[3-(2-methyl-pyrrolidin-1-ylmethyl)-pyrrolidin-1-yl]-phenyl}-amide

The title compound was prepared in a manner substantially the same asExample 1 by coupling2-methyl-4-[3-(2-methyl-pyrrolidin-1-ylmethyl)-pyrrolidin-1-yl]-phenylaminewith 2,5-dioxo-2,3,4,5-tetrahydro-1H-benzo[e][1,4]diazepine-8-carboxylicacid. MS: 476.3 (M+H).

Example 14 Pyridine-2,5-dicarboxylic acid2-[(2-methoxy-ethyl)-amide]5-({2-methyl-4-[3-(2-methyl-pyrrolidin-1-ylmethyl)-pyrrolidin-1-yl]-phenyl}-amide)

The title compound was prepared in a manner substantially the same asExample 1 by coupling2-methyl-4-[3-(2-methyl-pyrrolidin-1-ylmethyl)-pyrrolidin-1-yl]-phenylaminewith pyridine-2,5-dicarboxylic acid 2-[(2-methoxy-ethyl)-amide]. MS:480.3 (M+H).

Example 15 6-Methoxy-benzofuran-2-carboxylic acid{2-methyl-4-[3-(2-methyl-pyrrolidin-1-ylmethyl)-pyrrolidin-1-yl]-phenyl}-amide

The title compound was prepared in a manner substantially the same asExample 1 by coupling2-methyl-4-[3-(2-methyl-pyrrolidin-1-ylmethyl)-pyrrolidin-1-yl]-phenylaminewith 6-methoxy-benzofuran-2-carboxylic acid. MS: 448.5 (M+H).

Example 16 3,4-Dihydroxy-2,2-dimethyl-chroman-6-carboxylic acid{2-methyl-4-[3-(2-methyl-pyrrolidin-1-ylmethyl)-pyrrolidin-1-yl]-phenyl}-amide

The title compound was prepared in a manner substantially the same asExample 1 by coupling2-methyl-4-[3-(2-methyl-pyrrolidin-1-ylmethyl)-pyrrolidin-1-yl]-phenylaminewith 3,4-Dihydroxy-2,2-dimethyl-chroman-6-carboxylic acid. MS: 494.6(M+H).

Example 17 4-Hydroxy-7-methyl-[1,8]naphthyridine-3-carboxylic acid{2-methyl-4-[3-(2-methyl-pyrrolidin-1-ylmethyl)-pyrrolidin-1-yl]-phenyl}-amide

The title compound was prepared in a manner substantially the same asExample 1 by coupling2-methyl-4-[3-(2-methyl-pyrrolidin-1-ylmethyl)-pyrrolidin-1-yl]-phenylaminewith 4-hydroxy-7-methyl-[1,8]naphthyridine-3-carboxylic acid. MS: 460.6(M+H).

Example 18N-{2-Methyl-4-[3-(2-methyl-pyrrolidin-1-ylmethyl)-pyrrolidin-1-yl]-phenyl}-4-(3-methyl-5-oxo-4,5-dihydro-pyrazol-1-yl)-benzamide

The title compound was prepared in a manner substantially the same asExample 1 by coupling2-methyl-4-[3-(2-methyl-pyrrolidin-1-ylmethyl)-pyrrolidin-1-yl]-phenylaminewith 4-(3-methyl-5-oxo-4,5-dihydro-pyrazol-1-yl)-benzoic acid. MS: 474.6(M+H).

Example 19 6-Methyl-4-oxo-4H-chromene-2-carboxylic acid{2-methyl-4-[3-(2-methyl-pyrrolidin-1-ylmethyl)-pyrrolidin-1-yl]-phenyl}-amide

The title compound was prepared in a manner substantially the same asExample 1 by coupling2-methyl-4-[3-(2-methyl-pyrrolidin-1-ylmethyl)-pyrrolidin-1-yl]-phenylaminewith 6-methyl-4-oxo-4H-chromene-2-carboxylic acid. MS: 460.3 (M+H).

Example 20(2S,3R)-5-Fluoro-2-methyl-N-{2-methyl-4-[3-(2-methyl-pyrrolidin-1-yl-methyl)-pyrrolidin-1-yl]-phenyl}-benzamide

(2S,3R)-2-Methyl-4-[3-(2-methyl-pyrrolidin-1-yl-methyl)-pyrrolidin-1-yl]-phenylamine(92 mg, 0.34 mmol) was dissolved in DCM (4 mL) and pyridine (1 mL). Thesolution was cooled in an ice-water bath. To this solution was added asolution of 5-fluoro-2-methylbenzoyl chloride (from Alfa Aesar, 0.48 g,2.77 mmol, 1.6 equiv.) in DCM (2 mL). The solution was stirred at r.t.for 2 h. The reaction was judged to be complete when TLC (10% MeOH inDCM) and LC/MS did not detect the SM at 274, but detected only theproduct peak at 410.2 and at retention time of 3.02 min. Polymer boundeddiethylenetriamine (4 mmol/g, 0.12 g) was added and stirred at r.t. for30 min., then filtered and rinsed with DCM. The solvent was evaporatedto dryness, re-dissolved in DCM and NaHCO₃ aqueous solution. The twolayers were separated, and the aqueous layer was extracted with DCM (10mL×2). The combined DCM extracts were successively washed with sodiumbicarbonate (5 mL) and brine (5 mL×2), dried (anhydrous potassiumcarbonate), passed through a silica gel pad (self packed, ˜10 g), rinsedwith DCM (no product) and then with 10% MeOH in DCM (contain product).The solution was concentrated in vacuo to obtain a crude product, whichwas purified on a silica gel column by eluting with 0 to 10% MeOH in DCMto obtain 48 mg (34% yield) of the title compound as a semi-solid.LC/MS: t=3.020 min, MS: 410.2. ¹H NMR (300 MHz, CDCl₃), δ (ppm): 7.49(m, 1H), 7.23 (m, 1H), 7.11 (m, 2H), 6.41 (m, 1H), 3.70 (m, 2H), 3.57(t, 6.2 Hz, 1H), 3.39 (m, 2H), 3.32 (m, 1H), 3.16 (m, 1H), 3.06 (m, 1H),2.95 (m, 2H), 2.65 (m, 1H), 2.62 (s, 1H), 2.61 (s, 3H), 2.49 (m, 1H),2.38 (s, 3H), 2.05 (m, 2H), 1.90 (m, 2H), 1.80 (m, 1H), 1.40 (d, 6.5 Hz,3H).

Example 21(2S,3R)-3-Fluoro-N-{2-methyl-4-[3-(2-methyl-pyrrolidin-1-yl-methyl)-pyrrolidin-1-yl]-phenyl}-benzamide

The title compound was prepared in a manner substantially the same asexample 20 by coupling(2S,3R)-2-methyl-4-[3-(2-methyl-pyrrolidin-1-yl-methyl)-pyrrolidin-1-yl]-phenylaminewith 3-fluoro-benzoyl chloride in 39% yield.

LCMS: RT=2.949 minutes, MS: 396.20 (M+H).

¹H NMR (CDCl₃, 300 MHz), δ (ppm): 7.87 (d, 7.7 Hz, 1H), 7.62 (m, 2H),7.45 (m, 2H), 7.20 (m, 1H), 6.39 (m, 1H), 3.73 (m, 1H), 3.57 (t, 6.2 Hz,1H), 3.59 (m, 1H), 3.40-3.19 (m, 3H), 3.07 (m, 2H), 2.82-2.68 (m, 3H),2.36 (m, 1H), 2.25 (s, 3H), 2.15 (m, 2H), 2.11-1.80 (m, 3H), 1.43 (d,6.4 Hz, 3H).

Example 22 (2S,3R)-Furan-3-carboxylic acid{2-methyl-4-[3-(2-methyl-pyrrolidin-1-yl-methyl)-pyrrolidin-1-yl]-phenyl}-amide

The title compound was prepared in a manner substantially the same asexample 20 by coupling(2S,3R)-2-methyl-4-[3-(2-methyl-pyrrolidin-1-yl-methyl)-pyrrolidin-1-yl]-phenylaminewith 3-furoyl chloride in 35% yield.

LCMS: RT=2.502 minutes, MS: 368.2 (M+H).

¹H NMR (CD₃OD, 300 MHz), δ (ppm): 8.16 (bs, 1H), 7.61 (bs, 1H), 7.08 (d,8.4 Hz, 1H), 6.90 (bs, 1H), 6.49 (m, 2H), 3.58 (m, 2H), 3.55-3.27 (m,3H), 3.08-2.92 (m, 2H), 2.70 (m, 1H), 2.35 (m, 3H), 2.28 (s, 3H), 2.15(m, 2H), 2.08 (m, 2H), 1.87 (m, 1H), 1.70 (m, 1H), 1.40 (d, 6.4 Hz, 3H).

Example 23 (2S,3R)-3,5-Dimethyl-isoxazole-4-carboxylic acid{2-methyl-4-[3-(2-methyl-pyrrolidin-1-yl-methyl)-pyrrolidin-1-yl]-phenyl}-amide

The title compound was prepared in a manner substantially the same asexample 20 by coupling(2S,3R)-2-methyl-4-[3-(2-methyl-pyrrolidin-1-yl-methyl)-pyrrolidin-1-yl]-phenylaminewith 3,5-dimethyIsoxazole-4-carbonyl chloride in 50% yield.

LCMS: RT=2.521 minutes, MS: 397.3 (M+H).

¹H NMR (CD₃OD, 300 MHz), δ (ppm): 7.46 (b, 1H), 6.92 (b, 1H), 6.39 (m,1H), 3.56 (m, 2H), 3.38 (m, 2H), 3.03 (m, 2H), 2.70 (m, 1H), 2.65 (s,3H), 2.44 (s, 3H), 2.25 (s, 3H), 2.68 (m, 3H), 2.15 (m, 3H), 2.08 (m,2H), 1.87 (m, 1H), 1.70 (m, 1H), 1.30 (d, 6.4 Hz, 3H).

Example 24 (2S,3R)-Cyclohexane carboxylic acid{2-methyl-4-[3-(2-methyl-pyrrolidin-1-yl-methyl)-pyrrolidin-1-yl]-phenyl}-amide

The title compound was prepared in a manner substantially the same asexample 20 by coupling(2S,3R)-2-methyl-4-[3-(2-methyl-pyrrolidin-1-yl-methyl)-pyrrolidin-1-yl]-phenylaminewith cyclohexanecarbonyl chloride in 45% yield.

LCMS: RT=2.972 minutes, MS: 384.2 (M+H).

Biological Examples Example 25

This Example demonstrates the efficacy of compounds of this invention asH3 receptor ligands. The compounds of this invention have beendemonstrated to displace [³H]-Methylhistamine radioligand binding tomammalian cell membranes expressing rhesus (Macacca Mulatta) H3receptor. These compounds display rhesus H3 affinity constants (Ki) inthe range of 1 μM to <1 nM. Additionally, the compounds of thisinvention have been demonstrated by GTPγS radioligand binding assay toinhibit rhesus H3 constitutive functional activity in cell membranes.This inhibition of basal rhesus H3-mediated GTPγS radioligand bindingdemonstrates that the compounds of this invention find utility asinverse agonists. These compounds decreased rhesus H3 GTPγS radioligandbinding by 0-40% below basal levels.

Rhesus H3 membranes were prepared from the Flp-In T-REx 293 Cell Line(Invitrogen) stably transfected with pcDNA5/FRT/TO (Invitrogen)containing the rhesus monkey (Macacca Mulatta) 445 amino acid H3receptor. (Genbank #AY231164). Stably transfected cultures wereamplified in tissue culture flasks by standard tissue culture methodsand induced to express rhesus H3 by exposure to 500 ng/ml tetracycline(Cellgro) for 24 hours. After induction, cells were dissociated fromflasks utilizing Cell Stripper (Cellgro). Cells were centrifuged (1K×g,5 min) and pellet frozen in an ethanol-dry ice bath to disrupt cellmembranes. Frozen cell pellet was re-suspended in 5 mM HEPES (pH 7.4,Invitrogen) at 10 ml/1000 cm2 of harvested cells. The cell suspensionwas drawn through an 18 gauge needle (2-3×) followed by a 23 gaugeneedle (2-3×) to further disrupt cell membranes. The cell suspension wascentrifuged (40K×g, 30 min). Cell membrane pellet was re-suspended in 5mM HEPES (pH 7.4, Invitrogen) at a final protein concentration of 10mg/ml. Rhesus H3 membranes were stored under liquid nitrogen prior touse in [3H]-Methylhistamine and GTPγS radioligand binding assays.

Rhesus H3 radioligand binding assay was performed using rhesus H3receptor membranes (prepared as described above), [3H]-Methylhistamine(Perkin Elmer) and WGA SPA beads (wheat germ agglutinin scintillationproximity assay) beads (Amersham). The assay was performed in 96-wellOpti-Plates (Packard). Each reaction contained 50 μl rhesus H3 membranes(20-30 μg total protein), 50 μl WGA SPA beads (0.1 μg) and 50 μl of83Ci/mmol [³H]-Methylhistamine (final concentration 2 nM) and 50 μl oftested compound. The compounds of this invention and/or vehicle werediluted with binding buffer from 10 mM DMSO stocks. Assay plates weresealed with TopSeal (Perkin Elmer) and mixed on shaker (25° C., 1 hour).Assay plates were read on TopCount scintillation counter (Packard).Results were analyzed by Hill transformation and Ki values weredetermined by Cheng-Prusoff equation. The observed binding data for afew of the representative compounds of this invention are summarized inTable 1.

TABLE 1 Affinity: ki in Inverse Agonism: % Rhesus H3 inhibition of Basalmembrane GTPγS binding in Example No. binding ki (nM) Rhesus H3 1 15.7 —2 51.2 — 3 94.7 — 4 39.3 — 5 40.4 — 6 95.4 — 7 34.2 — 8 18.0 — 9 3.1 —10 29.8 — 11 62.1 — 12 61.5 — 13 9.3 — 14 32.3 — 15 66.7 — 16 67.6 — 1719.2 — 18 59.4 — 19 26.5 —

Example 26

This Example illustrates selective affinity of the compounds of thisinvention at H3 receptors and exhibit low activity at the MCH-1 receptorsite.

The H3 affinity of the compounds of this invention was measured inaccordance with the procedures set forth in Example 25.

The activity of the compounds of this invention at the MCH-1 receptorsite, if any was measured by the procedures as set forth below.

Test Compounds: The compounds of this invention were stored in a 96-wellmicrotiter plates (1 μL, 10 mM, 100% DMSO). Each of the test sample wasdiluted with 249 μL of 100% DMSO (dilution 1:250). The test compoundswere further diluted 1:4 (0.1% DMSO) during assay resulting in the finalconcentration of test compounds of this invention to be 10 μM.Negative Control: 40 μM of MCH-1 in assay buffer with 0.4% DMSO weretransferred to the dilution microtiter plates for control which resultedin final concentration of 10 μM.Blank: Assay buffer containing 0.4% DMSO were transferred to thedilution microtiter plates for blanksAssay Procedure: The filter plates with 250 mL of 0.5% PEI-solution/wellwere incubated for 2 hours at room temperature. PEI was removed byvacuum filtration just before pipetting (Univac Polyfiltronic/Whatman).The solution of the compound as prepared above (50 μL), or MCH-1(negative control) or Puffer/DMSO (positive control) were added to96-well round bottom microtiter plate. Then 50 μl of [¹²⁵J]-ligandsolution was added followed by 100 μl of membrane suspension. The plateswere closed with the lids, and incubated for 60 min. at 25° C. Thesamples were transferred to GF/B filter plate. The reaction mixture wasremoved by vacuum filtration, washed 4× with 300 μl ice-cold washingbuffer and the washing solution was removed by vacuum filtration. Therubber layer at the bottom of the plate was then removed and the filterswere dried over night at room temperature. 25 μl of scintillationcocktail was added and the plates were sealed and, plate frames wereadded and incubated for 1 hour at room temperature. The radioactivitywas then measured, settings ¹²⁵J standard, 30 sec./well. From this thepercent inhibition of ligand binding was measured.Results: In general the compounds of this invention exhibited a rhesusH3 binding ki value in the range of from about 100 nM to less than 5 nM,whereas the percent inhibition of ligand binding at MCH-1 receptor wasless than 35% at 10 μM concentration. This comparative Exampledemonstrates that the compounds of this invention can be more thanthousand times more selective at H3 receptor site than at MCH-1 receptorsite.

Example 27

This Example illustrates the study of efficacy of the compounds of thisinvention in increasing the wakefulness in animal models.

Male Sprague Dawley rats (Charles River, France) weighing 250±10 g wereanaesthetized with Zoletil® 50 (60 mg/kg ip) and mounted in astereotaxic apparatus. Cortical electrodes (small stainless steel screwelectrodes of 0.9 mm in diameter) were screwed into the bone over thesensorimotor cortex (1.5 mm lateral to the median suture and 1.5 mmbehind the fronto-parietal suture), the visual cortex (1.5 mm lateral tothe median suture and 1.5 mm in front of the parieto-occipital suture)and over the cerebellum (reference electrode). Cortical electrodes wereattached to a connector (Winchester, 7-lead) and fixed with dentalcement to the cranium.

After three weeks of post-operative recovery, animals were placed inplexiglass cylinders (60 cm diameter) with free access to food andwater. The temperature of the room was kept constant (21±1° C.) andlights were on from 7 a.m. to 7 p.m. The rats were recorded from 10 a.m.to 4 p.m. during three consecutive days: control day (D1), drug day (D2)and post drug day (D3). Vehicle (D1 and D3) or drug (D2) wereadministered 15 min before the recording.

Activity in sensorimotor and visual cortices were recorded by comparisonwith the reference electrode placed over the cerebellar cortex. Threestages were differentiated:

-   -   wakefulness (W) characterized by low voltage fast        electrocortical (ECoG) activity;    -   NREM sleep (non rapid eye movement or slow wave sleep: SWS)        characterized by an increase in electrocortical activity;        development of high-amplitude slow waves with some bursts of        sleep spindles;    -   REM sleep (rapid eye movement or paradoxical sleep: PS)        characterized by hypersynchronization of the theta rhythm in the        visual area.

Analysis of the ECoG signal was performed automatically by means of acomputerized system discriminating between the various sleep phasesusing sequential spectral analysis of ten seconds periods (Deltamed'ssoftware “Coherence”).

The compounds of this invention were dissolved in 0.6% MTC tween andadministered by oral route (po). The volume of injection was 0.5 ml/100g of body weight.

Two types of analysis were used to quantify the effects of the compoundsof this invention on sleep-wakefulness variables: the one hour-periodand the six hour-period analysis.

The results are expressed in minutes (one hour-period analysis) or asthe percentage of the control values (100%). Statistical analysis of thedata was carried out using the Student's t test for paired values todetermine significant variations from control values.

Example 28 Stress-induced Ultrasonic Vocalizations Test in Adult Rats

This Example illustrates the study of efficacy of the compounds of thisinvention as antidepressive agents in animal models.

The procedure used was adapted from the technique described by Van DerPoel A. M, Noach E. J. K, Miczek K. A (1989) Temporal patterning ofultrasonic distress calls in the adult rat: effects of morphine andbenzodiazepines. Psychopharmacology 97:147-8. Rats were placed for atraining session in a cage with a stainless steel grid floor (MEDAssociates, Inc., St. Albans, Vt.). Four electric shocks (0.8 mA, 3 s)were delivered every 7 s and ultrasonic vocalizations (UV, 22 KHz) weresubsequently recorded with the Ultravox system (Noldus, Wageningen, TheNetherlands) during 2 min. A modified ultrasound detector (Mini-3 batmodel) connected to a microphone was used to transform ultrasonic soundinto audible sound. The signal was then filtered and sent to a computerwhere the Ultravox software recorded each bout of UV that lasted morethan 10 ms. Rats were selected on the basis of their UV duration (>40 s)and subjected to the test, 4 h after training for the test, rats wereplaced in the same cage as that used for training One electric shock(0.8 mA, 3 s) was delivered and UV (duration and frequency) weresubsequently recorded with the Ultravox system during 2 min. Thecompounds of this invention were administered p.o. 60 min beforetesting.

Example 29 Forced-swimming Test in Rats

This Example further illustrates the study of efficacy of the compoundsof this invention as antidepressive agents in animal models.

The procedure was a modification of that described by Porsolt et al.(1977) Depression: a new animal model sensitive to antidepressanttreatments. Nature 266:730-2. Rats were placed in individual glasscylinder (40 cm height, 17 cm diameter) containing water (21° C.) to aheight of 30 cm. Two swimming sessions were conducted (a 15-min trainingsession followed 24 h later by a 6-min test). After each swimmingsession, rats were placed under a heating lamp to avoid hypothermia. Theduration of immobility was measured during the 6-min test. The compoundsof this invention were administered p.o. twice (15 min after trainingsession and 60 min before the test).

Although the invention has been illustrated by certain of the precedingexamples, it is not to be construed as being limited thereby; butrather, the invention encompasses the generic area as hereinbeforedisclosed. Various modifications and embodiments can be made withoutdeparting from the spirit and scope thereof.

1. A compound of formula (I):

wherein R, R₁, R₂ and R₃ are the same or different and independently ofeach other chosen from hydrogen, (C₁-C₄)alkyl or CF₃; R₄ is selectedfrom the group consisting of phenyl, cyclohexyl, pyridinyl, furanyl,isoxazolyl, quinolinyl, naphthyridinyl, indolyl, benzoimidazolyl,benzofuranyl, chromanyl, 4-oxo-4H-chromenyl, 2,3-dihydro-benzofuranyl,benzo[1,3]dioxolyl and2,5-dioxo-2,3,4,5-tetrahydro-1H-benzo[e][1,4]diazepinyl; wherein said R₄is optionally substituted one or more times with a substituent selectedfrom halogen, hydroxy, (C₁-C₄)alkyl, (C₁-C₄)alkoxy, CF₃, hydroxymethyl,2-hydroxyethylamino, methoxyethylamide, benzyloxymethyl, piperidinyl,N-acetyl-piperidinyl, pyrrolyl, imidazolyl and5-oxo-4,5-dihydro-pyrazolyl; or a salt thereof or an enantiomer or adiastereomer thereof.
 2. The compound according to claim 1, wherein Rand R₂ are methyl; and R₁ and R₃ are hydrogen.
 3. The compound accordingto claim 1, wherein R₄ is phenyl, wherein phenyl is optionallysubstituted with one or more groups selected from fluorine, methyl,hydroxymethyl, N-acetyl-piperidinyl, imidazolyl or5-oxo-4,5-dihydro-pyrazolyl.
 4. The compound according to claim 1,wherein R₄ is pyridinyl which is optionally substituted one or moretimes with chlorine, 2-hydroxyethylamino, methoxyethylamide,benzyloxymethyl or pyrrolyl.
 5. The compound according to claim 1,wherein R₄ is quinolinyl, naphthyridinyl, indolyl, benzoimidazolyl orbenzofuranyl, and wherein said R₄ is optionally substituted one or moretimes with chlorine, hydroxy, methyl or methoxy.
 6. The compoundaccording to claim 1, wherein R₄ is chromanyl, 4-oxo-4H-chromenyl or2,3-dihydro-benzofuranyl, wherein said R₄ is optionally substituted oneor more times with hydroxy or methyl.
 7. The compound according to claim1, wherein R₄ is benzo[1,3]dioxolyl or2,5-dioxo-2,3,4,5-tetrahydro-1H-benzo[e][1,4]diazepinyl.
 8. The compoundof claim 1 selected from the group consisting of:(2S,3R)-3-fluoro-N-{2-methyl-4-[3-(2-methyl-pyrrolidin-1-yl-methyl)-pyrrolidin-1-yl]-phenyl}-benzamide;(2S,3R)-5-fluoro-2-methyl-N-{2-methyl-4-[3-(2-methyl-pyrrolidin-1-yl-methyl)-pyrrolidin-1-yl]-phenyl}-benzamide;4-hydroxymethyl-N-{2-methyl-4-[3-(2-methyl-pyrrolidin-1-ylmethyl)-pyrrolidin-1-yl]-phenyl}-benzamide;4-imidazol-1-yl-N-{2-methyl-4-[3-(2-methyl-pyrrolidin-1-ylmethyl)-pyrrolidin-1-yl]-phenyl}-benzamide;4-(1-acetyl-piperidin-3-yl)-N-{2-methyl-4-[3-(2-methyl-pyrrolidin-1-ylmethyl)-pyrrolidin-1-yl]-phenyl}-benzamide;N-{2-methyl-4-[3-(2-methyl-pyrrolidin-1-ylmethyl)-pyrrolidin-1-yl]-phenyl}-4-(3-methyl-5-oxo-4,5-dihydro-pyrazol-1-yl)-benzamide;(2S,3R)-cyclohexanecarboxylic acid{2-methyl-4-[3-(2-methyl-pyrrolidin-1-yl-methyl)-pyrrolidin-1-yl]-phenyl}-amide;5-chloro-6-(2-hydroxy-ethylamino)-N-{2-methyl-4-[3-(2-methyl-pyrrolidin-1-ylmethyl)-pyrrolidin-1-yl]-phenyl}-nicotinamide;pyridine-2,5-dicarboxylic acid2-[(2-methoxy-ethyl)-amide]5-({2-methyl-4-[3-(2-methyl-pyrrolidin-1-ylmethyl)-pyrrolidin-1-yl]-phenyl}-amide);N-{2-methyl-4-[3-(2-methyl-pyrrolidin-1-ylmethyl)-pyrrolidin-1-yl]-phenyl}-6-pyrrol-1-yl-nicotinamide;6-benzyloxymethyl-N-{2-methyl-4-[3-(2-methyl-pyrrolidin-1-ylmethyl)-pyrrolidin-1-yl]-phenyl}-nicotinamide;(2S,3R)-furan-3-carboxylic acid{2-methyl-4-[3-(2-methyl-pyrrolidin-1-yl-methyl)-pyrrolidin-1-yl]-phenyl}-amide;(2S,3R)-3,5-dimethyl-isoxazole-4-carboxylic acid{2-methyl-4-[3-(2-methyl-pyrrolidin-1-yl-methyl)-pyrrolidin-1-yl]-phenyl}-amide;7-chloro-4-hydroxy-quinoline-3-carboxylic acid{2-methyl-4-[3-(2-methyl-pyrrolidin-1-ylmethyl)-pyrrolidin-1-yl]-phenyl}-amide;4-hydroxy-7-methyl-[1,8]naphthyridine-3-carboxylic acid{2-methyl-4-[3-(2-methyl-pyrrolidin-1-ylmethyl)-pyrrolidin-1-yl]-phenyl}-amide;1H-indole-6-carboxylic acid{2-methyl-4-[3-(2-methyl-pyrrolidin-1-ylmethyl)-pyrrolidin-1-yl]-phenyl}-amide;5-methoxy-1H-indole-2-carboxylic acid{2-methyl-4-[3-(2-methyl-pyrrolidin-1-ylmethyl)-pyrrolidin-1-yl]-phenyl}-amide;2-methyl-1H-benzoimidazole-5-carboxylic acid{2-methyl-4-[3-(2-methyl-pyrrolidin-1-ylmethyl)-pyrrolidin-1-yl]-phenyl}-amide;6-methoxy-benzofuran-2-carboxylic acid{2-methyl-4-[3-(2-methyl-pyrrolidin-1-ylmethyl)-pyrrolidin-1-yl]-phenyl}-amide;3,4-dihydroxy-2,2-dimethyl-chroman-6-carboxylic acid{2-methyl-4-[3-(2-methyl-pyrrolidin-1-ylmethyl)-pyrrolidin-1-yl]-phenyl}-amide;6-methyl-4-oxo-4H-chromene-2-carboxylic acid{2-methyl-4-[3-(2-methyl-pyrrolidin-1-ylmethyl)-pyrrolidin-1-yl]-phenyl}-amide;2,3-dihydro-benzofuran-5-carboxylic acid{2-methyl-4-[3-(2-methyl-pyrrolidin-1-ylmethyl)-pyrrolidin-1-yl]-phenyl}-amide;benzo[1,3]dioxole-5-carboxylic acid{2-methyl-4-[3-(2-methyl-pyrrolidin-1-ylmethyl)-pyrrolidin-1-yl]-phenyl}-amide;and 2,5-dioxo-2,3,4,5-tetrahydro-1H-benzo[e][1,4]diazepine-8-carboxylicacid{2-methyl-4-[3-(2-methyl-pyrrolidin-1-ylmethyl)-pyrrolidin-1-yl]-phenyl}-amide;or a pharmaceutically acceptable salt thereof.
 9. The compound of claim1 selected from the group consisting of:(2S,3R)-3-fluoro-N-{2-methyl-4-[3-(2-methyl-pyrrolidin-1-yl-methyl)-pyrrolidin-1-yl]-phenyl}-benzamide(2S,3R)-5-fluoro-2-methyl-N-{2-methyl-4-[3-(2-methyl-pyrrolidin-1-yl-methyl)-pyrrolidin-1-yl]-phenyl}-benzamide;4-hydroxymethyl-N-{2-methyl-4-[3-(2-methyl-pyrrolidin-1-ylmethyl)-pyrrolidin-1-yl]-phenyl}-benzamide;4-imidazol-1-yl-N-{2-methyl-4-[3-(2-methyl-pyrrolidin-1-ylmethyl)-pyrrolidin-1-yl]-phenyl}-benzamide;4-(1-acetyl-piperidin-3-yl)-N-{2-methyl-4-[3-(2-methyl-pyrrolidin-1-ylmethyl)-pyrrolidin-1-yl]-phenyl}-benzamide;N-{2-methyl-4-[3-(2-methyl-pyrrolidin-1-ylmethyl)-pyrrolidin-1-yl]-phenyl}-4-(3-methyl-5-oxo-4,5-dihydro-pyrazol-1-yl)-benzamide; (2S,3R)-cyclohexanecarboxylic acid{2-methyl-4-[3-(2-methyl-pyrrolidin-1-yl-methyl)-pyrrolidin-1-yl]-phenyl}-amide;5-chloro-6-(2-hydroxy-ethylamino)-N-{2-methyl-4-[3-(2-methyl-pyrrolidin-1-ylmethyl)-pyrrolidin-1-yl]-phenyl}-nicotinamide;pyridine-2,5-dicarboxylic acid2-[(2-methoxy-ethyl)-amide]5-({2-methyl-4-[3-(2-methyl-pyrrolidin-1-ylmethyl)-pyrrolidin-1-yl]-phenyl}-amide);N-{2-methyl-4-[3-(2-methyl-pyrrolidin-1-ylmethyl)-pyrrolidin-1-yl]-phenyl}-6-pyrrol-1-yl-nicotinamide;6-benzyloxymethyl-N-{2-methyl-4-[3-(2-methyl-pyrrolidin-1-ylmethyl)-pyrrolidin-1-yl]-phenyl}-nicotinamide;(2S,3R)-furan-3-carboxylic acid{2-methyl-4-[3-(2-methyl-pyrrolidin-1-yl-methyl)-pyrrolidin-1-yl]-phenyl}-amide;(2S,3R)-3,5-dimethyl-isoxazole-4-carboxylic acid{2-methyl-4-[3-(2-methyl-pyrrolidin-1-yl-methyl)-pyrrolidin-1-yl]-phenyl}-amide;7-chloro-4-hydroxy-quinoline-3-carboxylic acid{2-methyl-4-[3-(2-methyl-pyrrolidin-1-ylmethyl)-pyrrolidin-1-yl]-phenyl}-amide;4-hydroxy-7-methyl-[1,8]naphthyridine-3-carboxylic acid{2-methyl-4-[3-(2-methyl-pyrrolidin-1-ylmethyl)-pyrrolidin-1-yl]-phenyl}-amide;1H-indole-6-carboxylic acid{2-methyl-4-[3-(2-methyl-pyrrolidin-1-ylmethyl)-pyrrolidin-1-yl]-phenyl}-amide;5-methoxy-1H-indole-2-carboxylic acid{2-methyl-4-[3-(2-methyl-pyrrolidin-1-ylmethyl)-pyrrolidin-1-yl]-phenyl}-amide;and 2-methyl-1H-benzoimidazole-5-carboxylic acid{2-methyl-4-[3-(2-methyl-pyrrolidin-1-ylmethyl)-pyrrolidin-1-yl]-phenyl}-amide;or a pharmaceutically acceptable salt thereof.
 10. The compound of claim1 selected from the group consisting of:(2S,3R)-3-fluoro-N-{2-methyl-4-[3-(2-methyl-pyrrolidin-1-yl-methyl)-pyrrolidin-1-yl]-phenyl}-benzamide(2S,3R)-5-fluoro-2-methyl-N-{2-methyl-4-[3-(2-methyl-pyrrolidin-1-yl-methyl)-pyrrolidin-1-yl]-phenyl}-benzamide;4-hydroxymethyl-N-{2-methyl-4-[3-(2-methyl-pyrrolidin-1-ylmethyl)-pyrrolidin-1-yl]-phenyl}-benzamide;4-imidazol-1-yl-N-{2-methyl-4-[3-(2-methyl-pyrrolidin-1-ylmethyl)-pyrrolidin-1-yl]-phenyl}-benzamide;4-(1-acetyl-piperidin-3-yl)-N-{2-methyl-4-[3-(2-methyl-pyrrolidin-1-ylmethyl)-pyrrolidin-1-yl]-phenyl}-benzamide;N-{2-methyl-4-[3-(2-methyl-pyrrolidin-1-ylmethyl)-pyrrolidin-1-yl]-phenyl}-4-(3-methyl-5-oxo-4,5-dihydro-pyrazol-1-yl)-benzamide;5-chloro-6-(2-hydroxy-ethylamino)-N-{2-methyl-4-[3-(2-methyl-pyrrolidin-1-ylmethyl)-pyrrolidin-1-yl]-phenyl}-nicotinamide;pyridine-2,5-dicarboxylic acid2-[(2-methoxy-ethyl)-amide]5-({2-methyl-4-[3-(2-methyl-pyrrolidin-1-ylmethyl)-pyrrolidin-1-yl]-phenyl}-amide);N-{2-methyl-4-[3-(2-methyl-pyrrolidin-1-ylmethyl)-pyrrolidin-1-yl]-phenyl}-6-pyrrol-1-yl-nicotinamide;and6-benzyloxymethyl-N-{2-methyl-4-[3-(2-methyl-pyrrolidin-1-ylmethyl)-pyrrolidin-1-yl]-phenyl}-nicotinamide;or a pharmaceutically acceptable salt thereof.
 11. A pharmaceuticalcomposition comprising a compound of formula (I):

wherein R, R₁, R₂ and R₃ are the same or different and independently ofeach other chosen from hydrogen, (C₁-C₄)alkyl or CF₃; R₄ is selectedfrom the group consisting of phenyl, cyclohexyl, pyridinyl, furanyl,isoxazolyl, quinolinyl, naphthyridinyl, indolyl, benzoimidazolyl,benzofuranyl, chromanyl, 4-oxo-4H-chromenyl, 2,3-dihydro-benzofuranyl,benzo[1,3]dioxolyl and2,5-dioxo-2,3,4,5-tetrahydro-1H-benzo[e][1,4]diazepinyl; wherein said R₄is optionally substituted one or more times with a substituent selectedfrom halogen, hydroxy, (C₁-C₄)alkyl, (C₁-C₄)alkoxy, CF₃, hydroxymethyl,2-hydroxyethylamino, methoxyethylamide, benzyloxymethyl, piperidinyl,N-acetyl-piperidinyl, pyrrolyl, imidazolyl and5-oxo-4,5-dihydro-pyrazolyl; or a pharmaceutically acceptable saltthereof or an enantiomer or a diastereomer thereof in combination withat least one pharmaceutically acceptable excipient, diluent or acarrier.
 12. The composition according to claim 11, wherein the compoundof formula (I) is selected from the group consisting of:(2S,3R)-3-fluoro-N-{2-methyl-4-[3-(2-methyl-pyrrolidin-1-yl-methyl)-pyrrolidin-1-yl]-phenyl}-benzamide;(2S,3R)-5-fluoro-2-methyl-N-{2-methyl-4-[3-(2-methyl-pyrrolidin-1-yl-methyl)-pyrrolidin-1-yl]-phenyl}-benzamide;4-hydroxymethyl-N-{2-methyl-4-[3-(2-methyl-pyrrolidin-1-ylmethyl)-pyrrolidin-1-yl]-phenyl}-benzamide;4-imidazol-1-yl-N-{2-methyl-4-[3-(2-methyl-pyrrolidin-1-ylmethyl)-pyrrolidin-1-yl]-phenyl}-benzamide;4-(1-acetyl-piperidin-3-yl)-N-{2-methyl-4-[3-(2-methyl-pyrrolidin-1-ylmethyl)-pyrrolidin-1-yl]-phenyl}-benzamide;N-{2-methyl-4-[3-(2-methyl-pyrrolidin-1-ylmethyl)-pyrrolidin-1-yl]-phenyl}-4-(3-methyl-5-oxo-4,5-dihydro-pyrazol-1-yl)-benzamide;(2S,3R)-cyclohexanecarboxylic acid{2-methyl-4-[3-(2-methyl-pyrrolidin-1-yl-methyl)-pyrrolidin-1-yl]-phenyl}-amide;5-chloro-6-(2-hydroxy-ethylamino)-N-{2-methyl-4-[3-(2-methyl-pyrrolidin-1-ylmethyl)-pyrrolidin-1-yl]-phenyl}-nicotinamide;pyridine-2,5-dicarboxylic acid2-[(2-methoxy-ethyl)-amide]5-({2-methyl-4-[3-(2-methyl-pyrrolidin-1-ylmethyl)-pyrrolidin-1-yl]-phenyl}-amide);N-{2-methyl-4-[3-(2-methyl-pyrrolidin-1-ylmethyl)-pyrrolidin-1-yl]-phenyl}-6-pyrrol-1-yl-nicotinamide;6-benzyloxymethyl-N-{2-methyl-4-[3-(2-methyl-pyrrolidin-1-ylmethyl)-pyrrolidin-1-yl]-phenyl}-nicotinamide;(2S,3R)-furan-3-carboxylic acid{2-methyl-4-[3-(2-methyl-pyrrolidin-1-yl-methyl)-pyrrolidin-1-yl]-phenyl}-amide;(2S,3R)-3,5-dimethyl-isoxazole-4-carboxylic acid{2-methyl-4-[3-(2-methyl-pyrrolidin-1-yl-methyl)-pyrrolidin-1-yl]-phenyl}-amide;7-chloro-4-hydroxy-quinoline-3-carboxylic acid{2-methyl-4-[3-(2-methyl-pyrrolidin-1-ylmethyl)-pyrrolidin-1-yl]-phenyl}-amide;4-hydroxy-7-methyl-[1,8]naphthyridine-3-carboxylic acid{2-methyl-4-[3-(2-methyl-pyrrolidin-1-ylmethyl)-pyrrolidin-1-yl]-phenyl}-amide;1H-indole-6-carboxylic acid{2-methyl-4-[3-(2-methyl-pyrrolidin-1-ylmethyl)-pyrrolidin-1-yl]-phenyl}-amide;5-methoxy-1H-indole-2-carboxylic acid{2-methyl-4-[3-(2-methyl-pyrrolidin-1-ylmethyl)-pyrrolidin-1-yl]-phenyl}-amide;2-methyl-1H-benzoimidazole-5-carboxylic acid{2-methyl-4-[3-(2-methyl-pyrrolidin-1-ylmethyl)-pyrrolidin-1-yl]-phenyl}-amide;6-methoxy-benzofuran-2-carboxylic acid{2-methyl-4-[3-(2-methyl-pyrrolidin-1-ylmethyl)-pyrrolidin-1-yl]-phenyl}-amide;3,4-dihydroxy-2,2-dimethyl-chroman-6-carboxylic acid{2-methyl-4-[3-(2-methyl-pyrrolidin-1-ylmethyl)-pyrrolidin-1-yl]-phenyl}-amide;6-methyl-4-oxo-4H-chromene-2-carboxylic acid{2-methyl-4-[3-(2-methyl-pyrrolidin-1-ylmethyl)-pyrrolidin-1-yl]-phenyl}-amide;2,3-dihydro-benzofuran-5-carboxylic acid{2-methyl-4-[3-(2-methyl-pyrrolidin-1-ylmethyl)-pyrrolidin-1-yl]-phenyl}-amide;benzo[1,3]dioxole-5-carboxylic acid{2-methyl-4-[3-(2-methyl-pyrrolidin-1-ylmethyl)-pyrrolidin-1-yl]-phenyl}-amide;and 2,5-dioxo-2,3,4,5-tetrahydro-1H-benzo[e][1,4]diazepine-8-carboxylicacid{2-methyl-4-[3-(2-methyl-pyrrolidin-1-ylmethyl)-pyrrolidin-1-yl]-phenyl}-amide;or a pharmaceutically acceptable salt thereof.
 13. The compositionaccording to claim 11, wherein the compound of formula (I) is selectedfrom the group consisting of:(2S,3R)-3-fluoro-N-{2-methyl-4-[3-(2-methyl-pyrrolidin-1-yl-methyl)-pyrrolidin-1-yl]-phenyl}-benzamide;(2S,3R)-5-fluoro-2-methyl-N-{2-methyl-4-[3-(2-methyl-pyrrolidin-1-yl-methyl)-pyrrolidin-1-yl]-phenyl}-benzamide;4-hydroxymethyl-N-{2-methyl-4-[3-(2-methyl-pyrrolidin-1-ylmethyl)-pyrrolidin-1-yl]-phenyl}-benzamide;4-imidazol-1-yl-N-{2-methyl-4-[3-(2-methyl-pyrrolidin-1-ylmethyl)-pyrrolidin-1-yl]-phenyl}-benzamide;4-(1-acetyl-piperidin-3-yl)-N-{2-methyl-4-[3-(2-methyl-pyrrolidin-1-ylmethyl)-pyrrolidin-1-yl]-phenyl}-benzamide;N-{2-methyl-4-[3-(2-methyl-pyrrolidin-1-ylmethyl)-pyrrolidin-1-yl]-phenyl}-4-(3-methyl-5-oxo-4,5-dihydro-pyrazol-1-yl)-benzamide;(2S,3R)-cyclohexanecarboxylic acid{2-methyl-4-[3-(2-methyl-pyrrolidin-1-yl-methyl)-pyrrolidin-1-yl]-phenyl}-amide;5-chloro-6-(2-hydroxy-ethylamino)-N-{2-methyl-4-[3-(2-methyl-pyrrolidin-1-ylmethyl)-pyrrolidin-1-yl]-phenyl}-nicotinamide;pyridine-2,5-dicarboxylic acid2-[(2-methoxy-ethyl)-amide]5-({2-methyl-4-[3-(2-methyl-pyrrolidin-1-ylmethyl)-pyrrolidin-1-yl]-phenyl}-amide);N-{2-methyl-4-[3-(2-methyl-pyrrolidin-1-ylmethyl)-pyrrolidin-1-yl]-phenyl}-6-pyrrol-1-yl-nicotinamide;6-benzyloxymethyl-N-{2-methyl-4-[3-(2-methyl-pyrrolidin-1-ylmethyl)-pyrrolidin-1-yl]-phenyl}-nicotinamide;(2S,3R)-furan-3-carboxylic acid{2-methyl-4-[3-(2-methyl-pyrrolidin-1-yl-methyl)-pyrrolidin-1-yl]-phenyl}-amide;(2S,3R)-3,5-dimethyl-isoxazole-4-carboxylic acid{2-methyl-4-[3-(2-methyl-pyrrolidin-1-yl-methyl)-pyrrolidin-1-yl]-phenyl}-amide;7-chloro-4-hydroxy-quinoline-3-carboxylic acid{2-methyl-4-[3-(2-methyl-pyrrolidin-1-ylmethyl)-pyrrolidin-1-yl]-phenyl}-amide;4-hydroxy-7-methyl-[1,8]naphthyridine-3-carboxylic acid{2-methyl-4-[3-(2-methyl-pyrrolidin-1-ylmethyl)-pyrrolidin-1-yl]-phenyl}-amide;1H-indole-6-carboxylic acid{2-methyl-4-[3-(2-methyl-pyrrolidin-1-ylmethyl)-pyrrolidin-1-yl]-phenyl}-amide;5-methoxy-1H-indole-2-carboxylic acid{2-methyl-4-[3-(2-methyl-pyrrolidin-1-ylmethyl)-pyrrolidin-1-yl]-phenyl}-amide;and 2-methyl-1H-benzoimidazole-5-carboxylic acid{2-methyl-4-[3-(2-methyl-pyrrolidin-1-ylmethyl)-pyrrolidin-1-yl]-phenyl}-amide;or a pharmaceutically acceptable salt thereof.
 14. The compositionaccording to claim 11, wherein the compound of formula (I) is selectedfrom the group consisting of:(2S,3R)-3-fluoro-N-{2-methyl-4-[3-(2-methyl-pyrrolidin-1-yl-methyl)-pyrrolidin-1-yl]-phenyl}-benzamide;(2S,3R)-5-fluoro-2-methyl-N-{2-methyl-4-[3-(2-methyl-pyrrolidin-1-yl-methyl)-pyrrolidin-1-yl]-phenyl}-benzamide;4-hydroxymethyl-N-{2-methyl-4-[3-(2-methyl-pyrrolidin-1-ylmethyl)-pyrrolidin-1-yl]-phenyl}-benzamide;4-imidazol-1-yl-N-{2-methyl-4-[3-(2-methyl-pyrrolidin-1-ylmethyl)-pyrrolidin-1-yl]-phenyl}-benzamide;4-(1-acetyl-piperidin-3-yl)-N-{2-methyl-4-[3-(2-methyl-pyrrolidin-1-ylmethyl)-pyrrolidin-1-yl]-phenyl}-benzamide;N-{2-methyl-4-[3-(2-methyl-pyrrolidin-1-ylmethyl)-pyrrolidin-1-yl]-phenyl}-4-(3-methyl-5-oxo-4,5-dihydro-pyrazol-1-yl)-benzamide;5-chloro-6-(2-hydroxy-ethylamino)-N-{2-methyl-4-[3-(2-methyl-pyrrolidin-1-ylmethyl)-pyrrolidin-1-yl]-phenyl}-nicotinamide;pyridine-2,5-dicarboxylic acid2-[(2-methoxy-ethyl)-amide]5-({2-methyl-4-[3-(2-methyl-pyrrolidin-1-ylmethyl)-pyrrolidin-1-yl]-phenyl}-amide);N-{2-methyl-4-[3-(2-methyl-pyrrolidin-1-ylmethyl)-pyrrolidin-1-yl]-phenyl}-6-pyrrol-1-yl-nicotinamide;and6-benzyloxymethyl-N-{2-methyl-4-[3-(2-methyl-pyrrolidin-1-ylmethyl)-pyrrolidin-1-yl]-phenyl}-nicotinamide;or a pharmaceutically acceptable salt thereof.
 15. A method of treatinga disease in a patient, said disease selected from the group consistingof sleep related disorder, dementia, Alzheimer's disease, multiplesclerosis, cognitive disorder, attention deficit hyperactivity disorder,depression and appetite suppression, comprising administering to saidpatient a therapeutically effective amount of a compound of formula (I):

wherein R, R₁, R₂ and R₃ are the same or different and independently ofeach other chosen from hydrogen, (C₁-C₄)alkyl or CF₃; R₄ is selectedfrom the group consisting of phenyl, cyclohexyl, pyridinyl, furanyl,isoxazolyl, quinolinyl, naphthyridinyl, indolyl, benzoimidazolyl,benzofuranyl, chromanyl, 4-oxo-4H-chromenyl, 2,3-dihydro-benzofuranyl,benzo[1,3]dioxolyl and2,5-dioxo-2,3,4,5-tetrahydro-1H-benzo[e][1,4]diazepinyl; wherein said R₄is optionally substituted one or more times with a substituent selectedfrom halogen, hydroxy, (C₁-C₄)alkyl, (C₁-C₄)alkoxy, CF₃, hydroxymethyl,2-hydroxyethylamino, methoxyethylamide, benzyloxymethyl, piperidinyl,N-acetyl-piperidinyl, pyrrolyl, imidazolyl and5-oxo-4,5-dihydro-pyrazolyl; or a pharmaceutically acceptable saltthereof or an enantiomer or a diastereomer thereof optionally incombination with at least one pharmaceutically acceptable excipient,diluent or a carrier.
 16. The method according to claim 15, wherein thesleep disorder is selected from the group consisting of narcolepsy,circadian rhythm sleep disorder, obstructive sleep apnea, periodic limbmovement and restless leg syndrome, excessive sleepiness and drowsinessdue to medication side-effect.
 17. The method according to claim 15,wherein the sleep disorder is narcolepsy.
 18. The method according toclaim 15, wherein the disease is cognitive disorder.
 19. The methodaccording to claim 15, wherein the disease is Alzheimer's disease. 20.The method according to claim 15, wherein the disease is depression. 21.The method according to claim 15, wherein the disease is dementia. 22.The method according to claim 15, wherein the compound of formula (I) isselected from the group consisting of:(2S,3R)-3-fluoro-N-{2-methyl-4-[3-(2-methyl-pyrrolidin-1-yl-methyl)-pyrrolidin-1-yl]-phenyl}-benzamide;(2S,3R)-5-fluoro-2-methyl-N-{2-methyl-4-[3-(2-methyl-pyrrolidin-1-yl-methyl)-pyrrolidin-1-yl]-phenyl}-benzamide;4-hydroxymethyl-N-{2-methyl-4-[3-(2-methyl-pyrrolidin-1-ylmethyl)-pyrrolidin-1-yl]-phenyl}-benzamide;4-imidazol-1-yl-N-{2-methyl-4-[3-(2-methyl-pyrrolidin-1-ylmethyl)-pyrrolidin-1-yl]-phenyl}-benzamide;4-(1-acetyl-piperidin-3-yl)-N-{2-methyl-4-[3-(2-methyl-pyrrolidin-1-ylmethyl)-pyrrolidin-1-yl]-phenyl}-benzamide;N-{2-methyl-4-[3-(2-methyl-pyrrolidin-1-ylmethyl)-pyrrolidin-1-yl]-phenyl}-4-(3-methyl-5-oxo-4,5-dihydro-pyrazol-1-yl)-benzamide;(2S,3R)-cyclohexanecarboxylic acid{2-methyl-4-[3-(2-methyl-pyrrolidin-1-yl-methyl)-pyrrolidin-1-yl]-phenyl}-amide;5-chloro-6-(2-hydroxy-ethylamino)-N-{2-methyl-4-[3-(2-methyl-pyrrolidin-1-ylmethyl)-pyrrolidin-1-yl]-phenyl}-nicotinamide;pyridine-2,5-dicarboxylic acid2-[(2-methoxy-ethyl)-amide]5-({2-methyl-4-[3-(2-methyl-pyrrolidin-1-ylmethyl)-pyrrolidin-1-yl]-phenyl}-amide);N-{2-methyl-4-[3-(2-methyl-pyrrolidin-1-ylmethyl)-pyrrolidin-1-yl]-phenyl}-6-pyrrol-1-yl-nicotinamide;6-benzyloxymethyl-N-{2-methyl-4-[3-(2-methyl-pyrrolidin-1-ylmethyl)-pyrrolidin-1-yl]-phenyl}-nicotinamide;(2S,3R)-furan-3-carboxylic acid{2-methyl-4-[3-(2-methyl-pyrrolidin-1-yl-methyl)-pyrrolidin-1-yl]-phenyl}-amide;(2S,3R)-3,5-dimethyl-isoxazole-4-carboxylic acid{2-methyl-4-[3-(2-methyl-pyrrolidin-1-yl-methyl)-pyrrolidin-1-yl]-phenyl}-amide;7-chloro-4-hydroxy-quinoline-3-carboxylic acid{2-methyl-4-[3-(2-methyl-pyrrolidin-1-ylmethyl)-pyrrolidin-1-yl]-phenyl}-amide;4-hydroxy-7-methyl-[1,8]naphthyridine-3-carboxylic acid{2-methyl-4-[3-(2-methyl-pyrrolidin-1-ylmethyl)-pyrrolidin-1-yl]-phenyl}-amide;1H-indole-6-carboxylic acid{2-methyl-4-[3-(2-methyl-pyrrolidin-1-ylmethyl)-pyrrolidin-1-yl]-phenyl}-amide;5-methoxy-1H-indole-2-carboxylic acid{2-methyl-4-[3-(2-methyl-pyrrolidin-1-ylmethyl)-pyrrolidin-1-yl]-phenyl}-amide;2-methyl-1H-benzoimidazole-5-carboxylic acid{2-methyl-4-[3-(2-methyl-pyrrolidin-1-ylmethyl)-pyrrolidin-1-yl]-phenyl}-amide;6-methoxy-benzofuran-2-carboxylic acid{2-methyl-4-[3-(2-methyl-pyrrolidin-1-ylmethyl)-pyrrolidin-1-yl]-phenyl}-amide;3,4-dihydroxy-2,2-dimethyl-chroman-6-carboxylic acid{2-methyl-4-[3-(2-methyl-pyrrolidin-1-ylmethyl)-pyrrolidin-1-yl]-phenyl}-amide;6-methyl-4-oxo-4H-chromene-2-carboxylic acid{2-methyl-4-[3-(2-methyl-pyrrolidin-1-ylmethyl)-pyrrolidin-1-yl]-phenyl}-amide;2,3-dihydro-benzofuran-5-carboxylic acid{2-methyl-4-[3-(2-methyl-pyrrolidin-1-ylmethyl)-pyrrolidin-1-yl]-phenyl}-amide;benzo[1,3]dioxole-5-carboxylic acid{2-methyl-4-[3-(2-methyl-pyrrolidin-1-ylmethyl)-pyrrolidin-1-yl]-phenyl}-amide;and 2,5-dioxo-2,3,4,5-tetrahydro-1H-benzo[e][1,4]diazepine-8-carboxylicacid{2-methyl-4-[3-(2-methyl-pyrrolidin-1-ylmethyl)-pyrrolidin-1-yl]-phenyl}-amide;or a pharmaceutically acceptable salt thereof.
 23. The method accordingto claim 15, wherein the compound of formula (I) is selected from thegroup consisting of:(2S,3R)-3-fluoro-N-{2-methyl-4-[3-(2-methyl-pyrrolidin-1-yl-methyl)-pyrrolidin-1-yl]-phenyl}-benzamide;(2S,3R)-5-fluoro-2-methyl-N-{2-methyl-4-[3-(2-methyl-pyrrolidin-1-yl-methyl)-pyrrolidin-1-yl]-phenyl}-benzamide;4-hydroxymethyl-N-{2-methyl-4-[3-(2-methyl-pyrrolidin-1-ylmethyl)-pyrrolidin-1-yl]-phenyl}-benzamide;4-imidazol-1-yl-N-{2-methyl-4-[3-(2-methyl-pyrrolidin-1-ylmethyl)-pyrrolidin-1-yl]-phenyl}-benzamide;4-(1-acetyl-piperidin-3-yl)-N-{2-methyl-4-[3-(2-methyl-pyrrolidin-1-ylmethyl)-pyrrolidin-1-yl]-phenyl}-benzamide;N-{2-methyl-4-[3-(2-methyl-pyrrolidin-1-ylmethyl)-pyrrolidin-1-yl]-phenyl}-4-(3-methyl-5-oxo-4,5-dihydro-pyrazol-1-yl)-benzamide; (2S,3R)-cyclohexanecarboxylic acid{2-methyl-4-[3-(2-methyl-pyrrolidin-1-yl-methyl)-pyrrolidin-1-yl]-phenyl}-amide;5-chloro-6-(2-hydroxy-ethylamino)-N-{2-methyl-4-[3-(2-methyl-pyrrolidin-1-ylmethyl)-pyrrolidin-1-yl]-phenyl}-nicotinamide;pyridine-2,5-dicarboxylic acid2-[(2-methoxy-ethyl)-amide]5-({2-methyl-4-[3-(2-methyl-pyrrolidin-1-ylmethyl)-pyrrolidin-1-yl]-phenyl}-amide);N-{2-methyl-4-[3-(2-methyl-pyrrolidin-1-ylmethyl)-pyrrolidin-1-yl]-phenyl}-6-pyrrol-1-yl-nicotinamide;6-benzyloxymethyl-N-{2-methyl-4-[3-(2-methyl-pyrrolidin-1-ylmethyl)-pyrrolidin-1-yl]-phenyl}-nicotinamide;(2S,3R)-furan-3-carboxylic acid{2-methyl-4-[3-(2-methyl-pyrrolidin-1-yl-methyl)-pyrrolidin-1-yl]-phenyl}-amide;(2S,3R)-3,5-dimethyl-isoxazole-4-carboxylic acid{2-methyl-4-[3-(2-methyl-pyrrolidin-1-yl-methyl)-pyrrolidin-1-yl]-phenyl}-amide;7-chloro-4-hydroxy-quinoline-3-carboxylic acid{2-methyl-4-[3-(2-methyl-pyrrolidin-1-ylmethyl)-pyrrolidin-1-yl]-phenyl}-amide;4-hydroxy-7-methyl-[1,8]naphthyridine-3-carboxylic acid{2-methyl-4-[3-(2-methyl-pyrrolidin-1-ylmethyl)-pyrrolidin-1-yl]-phenyl}-amide;1H-indole-6-carboxylic acid{2-methyl-4-[3-(2-methyl-pyrrolidin-1-ylmethyl)-pyrrolidin-1-yl]-phenyl}-amide;5-methoxy-1H-indole-2-carboxylic acid{2-methyl-4-[3-(2-methyl-pyrrolidin-1-ylmethyl)-pyrrolidin-1-yl]-phenyl}-amide;and 2-methyl-1H-benzoimidazole-5-carboxylic acid{2-methyl-4-[3-(2-methyl-pyrrolidin-1-ylmethyl)-pyrrolidin-1-yl]-phenyl}-amide;or a pharmaceutically acceptable salt thereof.
 24. The method accordingto claim 15, wherein the compound of formula (I) is selected from thegroup consisting of:(2S,3R)-3-fluoro-N-{2-methyl-4-[3-(2-methyl-pyrrolidin-1-yl-methyl)-pyrrolidin-1-yl]-phenyl}-benzamide;(2S,3R)-5-fluoro-2-methyl-N-{2-methyl-4-[3-(2-methyl-pyrrolidin-1-yl-methyl)-pyrrolidin-1-yl]-phenyl}-benzamide;4-hydroxymethyl-N-{2-methyl-4-[3-(2-methyl-pyrrolidin-1-ylmethyl)-pyrrolidin-1-yl]-phenyl}-benzamide;4-imidazol-1-yl-N-{2-methyl-4-[3-(2-methyl-pyrrolidin-1-ylmethyl)-pyrrolidin-1-yl]-phenyl}-benzamide;4-(1-acetyl-piperidin-3-yl)-N-{2-methyl-4-[3-(2-methyl-pyrrolidin-1-ylmethyl)-pyrrolidin-1-yl]-phenyl}-benzamide;N-{2-methyl-4-[3-(2-methyl-pyrrolidin-1-ylmethyl)-pyrrolidin-1-yl]-phenyl}-4-(3-methyl-5-oxo-4,5-dihydro-pyrazol-1-yl)-benzamide;5-chloro-6-(2-hydroxy-ethylamino)-N-{2-methyl-4-[3-(2-methyl-pyrrolidin-1-ylmethyl)-pyrrolidin-1-yl]-phenyl}-nicotinamide;pyridine-2,5-dicarboxylic acid2-[(2-methoxy-ethyl)-amide]5-({2-methyl-4-[3-(2-methyl-pyrrolidin-1-ylmethyl)-pyrrolidin-1-yl]-phenyl}-amide);N-{2-methyl-4-[3-(2-methyl-pyrrolidin-1-ylmethyl)-pyrrolidin-1-yl]-phenyl}-6-pyrrol-1-yl-nicotinamide;and6-benzyloxymethyl-N-{2-methyl-4-[3-(2-methyl-pyrrolidin-1-ylmethyl)-pyrrolidin-1-yl]-phenyl}-nicotinamide;or a pharmaceutically acceptable salt thereof.
 25. The method accordingto claim 15, wherein the compound is having the formula (II):

wherein R, R₁, R₂, R₃ and R₄ are as defined in claim 15.